KR940010411B1 - Pharmaceutical composition comprising azabicyclo quinolone carboxylic acids - Google Patents

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Description

Pharmaceutical composition containing azabicyclo quinolone carboxylic acid

The present invention relates to novel 7-azabicyclo-substituted quinolone carboxylic acids, pharmaceutical compositions containing these compounds and methods of treatment using the compounds.

US Pat. No. 4,571,396 describes diazabicyclo substituted naphthyridine-, quinoline- and benzoxazine carboxylic acids with antimicrobial activity. European Patent Publication No. 215650 describes similar antibacterial diazabicyclo-substituted compounds.

The present invention provides prodrugs of an antibacterial compound having the general formula (I) or a compound of the general formula (I) having a pharmaceutically acceptable acid addition salt and free amino group thereof.

Wherein R ¹ is hydrogen, a pharmaceutically acceptable cation, or (C ₁ -C ₆ ) alkyl, Y is independently ethyl, t-butyl, vinyl, cyclopropyl, 2-fluoroethyl, p-fluoro Rophenyl, or O, P-difluorophenyl, W is hydrogen, F, Cl, Br, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, NH ₂ , NHCH ₃ , A is CH, CF , CCl, COCH ₃ , C-CH ₃ , C-CN or N or A together with Y and A and Y bonded carbon and nitrogen as carbons form a five or six membered ring, the ring being oxygen Or may contain a double bond, R ^{8 which} is methyl or methylene may be bonded, and R ² is Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ²⁵ are each independently H, CH ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ or CH ₂ NHC ₂ H ₅ and R ⁵ , R ⁶ , R ⁷ and R ⁹ may also be independently NH ₃ , NHCH ₃ or NHC ₂ H ₅ , provided that R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R Three or less of ⁹ , R ¹⁰ and R ²⁵ are other than hydrogen, and when three of these substituents are not hydrogen, at least one of them is methyl.

Preferred compounds of the invention are compounds of formula (I) and hydrates thereof, wherein R ¹ is hydrogen or a pharmaceutically acceptable cation such as sodium or potassium. Other preferred compounds are p-toluenesulfonate, methanesulfonate and hydrochloride salts of compounds of general formula (I).

Other preferred compounds are those in which A is CH or A, or A is a carbon, together with Y and the carbon and nitrogen to which A and Y are bonded, to form the following six-membered ring.

More preferably, A is CH or N, and most preferably A is N. More specific compounds are compounds in which one or two of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ²⁵ are other than hydrogen. More specific compounds in which one of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ^{10 is} CH ₂ NH ₂ or CH ₂ NHCH ₃ , optionally R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Another of R ⁹ and R ¹⁰ is methyl, or one of R ⁵ , R ⁶ , R ⁷ or R ^{9 is} NH ₂ or NHCH ₃ , and optionally any of R ⁵ , R ⁶ , R ⁷ or R ⁹ The other or one of R ³ , R ⁴ or R ¹⁰ is methyl rather than hydrogen. Preference is given to compounds wherein R ⁶ , R ⁷ or R ⁹ are amino and optionally one of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ or R ¹⁰ is methyl, more preferably R ⁷ is Amino and optionally one of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ or R ^{10 is} methyl. Most preferred compounds are those wherein R ⁷ is amino and R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are each hydrogen.

Other preferred compounds are compounds of compound (I) wherein Y is cyclopropyl or o, p-difluorophenyl and W is hydrogen.

Specific compounds of the invention are 7- (1-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4 -Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, 7-([1α, 2β, 5α, 6α] -6-amino-2-methyl-3-azabicyclo [3.1.0 ] -Hex-3-yl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid , 7-([1α, 6α, 7α] -7-amino-3-azabicyclo [4.1.0] -hept-3-yl) -6-fluoro-1- (2, 4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7-([1α, 6α, 7α] -7-amino-3-azabicyclo [4.1.0] hept -3-yl) -1-cycloflophyll] -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine 3-carboxylic acid, 7- (1-amino-3-azabicyclo [4.1.0] -hept-3-yl ) -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid, 7-([1α, 5α, 6α) -6-[(N-methyl) -Amino] -3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1 , 8-naphthyridine-3-carboxylic acid, 7- [1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- ( 2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, 7-([1α, 5α, 6α] -6-amino-3 Azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine -3-carboxylic acid, hydrate, 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, hydrochloride, methanesulfonate, 7-([1α, 5α, 6α] -6 -Amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2, 4-difluoro Nil) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 7-([1α, 5α, 6α] -6-aminomethyl-3-azabicyclo [3.1. 0] hex-3-yl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid to be.

Compounds of the general formula (I) of the present invention wherein R ³ , R ⁴ , R ⁵ , R ⁷ , R ¹⁰ and R ²⁵ are other than hydrogen, have these substituents in two stereo configurations to the cyclopropyl group in substituent R ² It can exist in one form. Compounds of formula (I) according to the invention comprise racemic mixtures and optical isomers of both of these arrangements.

The present invention includes prodrugs of compounds of formula (I) having free amino groups. Prodrugs are understood as amino acid residues, or polypeptide chains of two or more amino acid residues covalently linked via peptide bonds. Useful amino acid residues include the 20 natural amino acids, 4-hydroxyproline, hydroxylysine, democin, isodemosin, 3-methylhistidine, norvaline, beta-alamine, gamma-aminobutyric acid, citrulline, specified by the three letter symbol. , Homocysteine, homoserine, ornithine and methionine sulfone. Preferred amino acid residues are those having a nonpolar group such as Ala, Val, Nval, Leu, Met, Gly, Pro, Phe, or a basic polar group such as Lys.

The present invention includes a pharmaceutical composition consisting of a pharmaceutically acceptable carrier or diluent and an antimicrobially effective amount of a compound of formula (I).

The present invention further encompasses a method of treating a host comprising administering to a host such as an animal or human having a bacterial infection an antimicrobial effective amount of a compound of formula (I) or a pharmaceutical composition as defined above.

The invention also includes intermediates useful for the preparation of compounds of general formula (I). Exemplary intermediates have the general formula:

Wherein Y ¹ is hydrogen or benzyl, R ¹³ is methyl, cyano, hydroxymethyl, carboxyl or CH ₂ NR ¹¹ R ¹² , where R ¹¹ is hydrogen, methyl or ethyl, and R ¹² is hydrogen , C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsul Phenyl, diphenylphosphonyl, p-toluenesulfonyl, or benzyl, provided that when Y ¹ is hydrogen, R ¹³ is methyl or CH ₂ NR ¹¹ R ^{12 as} defined above),

Wherein Y ¹ is hydrogen or benzyl, R ¹⁴ is hydroxymethyl, CH ₂ NR ¹¹ R ¹² or NR ¹¹ R ¹² , where R ¹¹ is hydrogen, methyl or ethyl, R ¹² is hydrogen, C _1- C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropynyl, vinyloxycarbonyl, o-nitrophenylsulfonyl, Diphenylphosphonyl, p-toluenesulfonyl, or benzyl),

Wherein Y ² is hydrogen, benzyl or benzyloxycarbonyl, R ¹⁵ is carboxyl, hydroxymethyl, CHO, CH ₂ NR ¹¹ R ¹² or NR ¹¹ R ¹² , where R ¹¹ is hydrogen, methyl or Ethyl, R ¹² is hydrogen, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropyranyl, vinyloxycar Carbonyl, o-nitrophenylsulfonyl, diphenylphosphonyl, p-toluenesulfonyl or benzyl),

Wherein Y ¹ is hydrogen or benzyl, R ¹⁶ is methyl, hydroxymethyl, CHO, hydroxymethyl tetrahydropyranylether, or CH ₂ NR ¹¹ R ¹² , and R ¹⁷ is methyl, cyano, carbo Carboxyl, hydroxymethyl or CH ₂ NR ¹¹ R ¹² , wherein R ¹¹ is hydrogen, methyl or ethyl, R ¹² is hydrogen, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, optionally substituted benzyl Oxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropynyl, vinyloxycarbonyl, o-nitrophenylsulfonyl, diphenylphosphonyl, p-toluenesulfonyl, or benzyl),

Wherein Y ² is hydrogen, benzyl or benzyloxycarbonyl, R ¹⁸ is methyl, cyano, hydroxymethyl, or CH ₂ NR ¹¹ R ¹² , R ¹⁹ is methyl, carboxyl, hydroxymethyl, CHO, hydroxymethyltetrahydro pyranyl ether, CH ₂ NR ¹¹ R ¹² or NR ¹¹ R ¹² , wherein R ¹¹ is hydrogen, methyl or ethyl, R ¹² is hydrogen, C ₁ -C ₆ acyl, C _2- C ₆ alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropynyl, vinyloxycarbonyl, o-nitrophenylsulfonyl, diphenylphosphonyl, p-toluenesul Polyvinyl, or benzyl),

Wherein Y ² is hydrogen, benzyl or benzyloxycarbonyl, R ¹⁶ is methyl, hydroxymethyl, CHO, hydroxymethyl tetrahydropyranylether, or CH ₂ NR ¹¹ R ¹² , and R ²⁰ is methyl , Carboxyl, hydroxymethyl, CHO, methoxy carbonyl, ethoxycarbonyl, CH ₂ NR ¹¹ R ¹² , or NR ¹¹ R ¹² , wherein R ¹¹ is hydrogen, methyl or ethyl, R ¹² is hydrogen, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropynyl, vinyloxycarbonyl, o-nitrophenylsulfonyl , Diphenylphosphonyl, p-toluenesulfonyl, or benzyl),

Wherein Y ² is hydrogen, benzyl or benzyloxycarbonyl, R ²¹ is methyl, carboxyl, hydroxymethyl, CHO, hydroxymethyl tetrahydropyranylether, t-butoxycarbonyl, CH ₂ NR ¹¹ R ¹² or NR ¹¹ R ¹² , R ²² is methyl, carboxyl, hydroxymethyl, CHO, ethoxycarbonyl, CH ₂ NR ¹¹ R ¹² , or NR ¹¹ R ¹² , wherein R ¹¹ is hydrogen, methyl Or ethyl, R ¹² is hydrogen, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropyridyl, vinyloxy Carbonyl, o-nitrophenylsulfonyl, diphenylphosphonyl, p-toluenesulfonyl, or benzyl),

Wherein Y ² is hydrogen, benzyl, or benzyloxycarbonyl, R ²³ is methyl, carboxyl, hydroxymethyl, CHO, methoxycarbonyl, CH ₂ NR ¹¹ R ¹² or NR ¹¹ R ¹² , R ²⁴ is methyl, carboxyl, hydroxymethyl, CHO, hydroxymethyl tetrahydropyranyl ether, CH ₂ NR ¹¹ R ¹² or NR ¹¹ R ¹² , wherein R ¹¹ is hydrogen, methyl or ethyl, and R ¹² is Hydrogen, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropynyl, vinyloxycarbonyl, o-nitrophenyl Sulfonyl, diphenylphosphonyl, p-toluenesulfonyl, or benzyl),

Wherein Y ¹ is hydrogen or benzyl, R ¹⁶ is methyl, hydroxymethyl, CHO, hydroxymethyl tetrahydropyranylether, or CH ₂ NR ¹¹ R ¹² , and R ¹⁷ is methyl, cyano, carbo Carboxyl, hydroxymethyl, CHO, or CH ₂ NR ¹¹ R ¹² , wherein R ¹¹ is hydrogen, methyl or ethyl, R ¹² is hydrogen, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, optionally Substituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropynyl, vinyloxycarbonyl, o-nitrophenylsulfonyl, diphenylphosphonyl, p-toluenesulfonyl, or benzyl).

Other intermediates useful for preparing compound (I) are evident in the specification, in particular in Roman numerals.

The term "C ₁ -C ₆ alkyl" as used in the definition of R ¹ refers to a straight or branched chain aliphatic saturated monovalent atom having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. It means a hydrocarbon group.

When A is carbon and Y and A and together with carbon and nitrogen to which each is bonded form a 5- or 6-membered ring, the compound of formula (I) has the following general formula.

Wherein Z is CH ₂ , O or a covalent bond, D is CH ₂ , CHCH ₃ or C = CH ₂ , and D may be CH = CH when Z is a covalent bond.

Compound (I) of the present invention is represented by the following general formula (II),

Of a compound can be prepared by reacting a compound of formula R ² H, and the R ^1, R ^2, R, A, W and Y in the formula R ² is ^{R 3, R 4, R 5} , R 6, R 9 , In the definitions of R ¹⁰ and R ¹¹ , except that they include N-protecting groups of NH ₂ , CH ₂ NH ₂ , NHCH ₃ , CH ₂ NHCH ₃ , NHC ₂ H ₅ and CH ₂ NHC ₂ H ₅ . Are as defined above with respect to X and X is a leaving group such as fluoro, chloro, bromo or C ₁ -C ₃ alkylsulfonyl. Nitrogen protecting groups are known in the art. Examples of suitable nitrogen protecting groups include C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, silyl, trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfonyl, diphenylphosphinyl, p-toluenesulfonyl and benzyl. Nitrogen protecting groups are removed by methods known in the art such as hydrogenation or hydrolysis.

The reaction can be carried out with or without a solvent. If a solvent is used, the solvent should be inert under the reaction conditions. Suitable solvents include acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethyl sulfoxide, dimethylformamide, pyridine, water or mixtures thereof.

The reaction temperature is typically about 20 ° to about 150 ° C.

The reaction can be advantageously carried out in the presence of an inorganic or organic base such as an alkali or alkaline earth metal carbonate or bicarbonate, or an acid acceptor such as a tertiary amine such as triethylamine, pyridine or picoline.

When R ¹ is C ₁ -C ₆ alkyl, the conversion to the corresponding acid can be performed at about 20 ° to 150 ° C., under acidic or basic conditions customary for hydrolysis of the carboxylic acid ester.

Starting materials of general formula (II) are known in the art, for example, in US Pat. Nos. 4,571,396 and 4,775,668. The starting material of formula R ² H has the general formula:

Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ²⁵ are as defined above in connection with the compound of formula R ² H.

Specific examples of such starting materials include the following compounds.

Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ²⁵ are as defined above except hydrogen.

The manufacturing method of the said typical compound (I)-(XXI) is described below, and the part of each manufacturing method is represented by the produced compound.

3-azabicyclo [3.1.0] hexane (V)

3-azabicyclo [3.1.0] hexane was obtained from 1, 2-cyclopropanedicarboxylic acid. a. It may be produced by the method of European Patent Publication No. 0010799 to D. A. Wood et al.

2-R ³ -substituted 3-azabicyclo [3.1.0] hexane (VI)

2-cyano-3-azabicyclo [3.1.0] hexane is di. a. It can be prepared by the method of European Patent Publication No. 0010799 such as DA Wood. For example, benzyl groups protect the ring nitrogen to yield 3-benzyl-2-cyano-3-azabicyclo [3.1.0] hexane. The nitrile is reduced with lithium aluminum hydride to obtain a compound of formula VI wherein R ³ is CH ₂ NH ₂ and 3-N is benzylated. This compound and all of the amino-substituted azabicyclo [3.1.0] hexyl groups described below are advantageously using, for example, alkoxycarbonyl groups such as tert-butoxy-carbonyl, or carboxylic acid groups such as formyl or acetyl. It can be protected and then debenzylated via hydrogenation to afford protected 2-aminomethyl-3-azabicyclo [3.1.0] hexane. After coupling this debenzylated diamine to the quinolone or naphthyridine nucleus by reacting with a compound of formula (II), amino-protecting groups such as tert-butoxy-carbonyl or acetyl groups can be removed by exposure to acidic conditions. have.

Alternatively, diamine 2-aminomethyl-3-benzyl-3-azabicyclo [3.1.0] hexane can be obtained from J. Org. Formylated or acetylated by heat reflux with ethyl formate or acetyl chloride according to the method of Chem., 27, 4058 (1962). These amides can then be reduced to the corresponding amines using lithium aluminum hydride to afford compounds of formula (VI) wherein R ³ is CH ₂ NHCH ₃ or CH ₂ NHC ₂ H ₅ . This compound is prepared by converting the diamine 2-aminomethyl-3-benzyl-3-azabicyclo [3.1.0] hexane to 2-[(N-acetyl) aminomethyl] or 2-[(N-tert-butoxycarbonyl) Protected as in the case of conversion to aminomethyl] -3-benzyl-3-azabicyclo [3.1.0] hexane, then added to the quinolone or naphthyridine nuclei by debenzylation and reaction with a compound of formula (II). You can.

When R ³ is CH ₃ , the nitrile 3-benzyl-2-cyano-3-azabicyclo [3.1.0] hexane is hydrolyzed to the corresponding carboxylic acid under acidic or basic conditions and is lithium aluminum hydride. It can be used to reduce to alcohol 3-benzyl-2-hydroxymethyl-3-azabicyclo [3.1.0] hexane. Subsequently, tosylate is again produced by lithium hydride aluminum reduction to yield 3-benzyl-2-methyl-3-azabicyclo [3.1.0] hexane, a 2-methyl homologue, which can be debenzylated as described above. have.

1-R ⁶ -substituted-3-azabicyclo [3.1.0] hexane (VII)

These compounds can be prepared from nitrile 3-benzyl-1-cyano-3-azabicyclo [3.1.0] hexane, the preparation of which is carried out by Achini and Oppolzer, Tetrahedron Letters, 1975. , 369. Alternatively, the nitrile can be synthesized via bismethylation from 3-[(benzyl) (2,3-dihydroxypropyl) amino] propanenitrile followed by double ring closure with sodium hexamethyldisilazide. The conversion of the nitrile functionality of 3-benzyl-1-cyano-3-azabicyclo [3.1.0] hexane to CH ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ or CH ₂ NHC ₂ H ₅ is in VI above. It can be done as follows.

Hydrolysis of 3-benzyl-1-cyano-3-azabicyclo [3.1.0] hexane to 3-benzyl-3-azabicyclo [3.1.0] hexane-1-carboxylic acid can be carried out under basic conditions. have. 3-benzyl-1-tert-butoxycarbonylamino, an amine protected by subsequent reaction with diphenylphosphoryl azide in t-butanol using the method described in Tetrahedron 1974, 30, 2151 by Ninomiya et al. 3-azabicyclo [3.1.0] hexane is provided. By debenzylation described above, the compound is reacted with the compound of formula (II) to obtain an amine which can be coupled to the quinolone or naphthyridine nucleus, and 3-azabicyclo [3.1.0] is obtained by acidic removal of the tert-butoxycarbonyl group. The final product with amino groups as 1-substituent in the hexane side chain is obtained.

1-amino-3-benzyl-3-azabicyclo [3.1.0] Removal of the t- portion from the protected amine to obtain a hexane-ethoxy carbonyl group leads to the above-acetylation or formylation and lithium aluminum hydride reduction R ⁶ A compound of formula (VII) wherein NH is ₃ or NHC ₂ H ₅ can be obtained. It is possible to obtain a final product containing methylamine or ethylamine in the C-1 of the 3-azabicyclo [3.1.0] hexane side chain by an additional process as in VI.

Alternatively, 3-benzyl-1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane can be N-alkylated by treatment with sodium hydride and methyl iodide or ethyl iodide. The resulting diprotective N-alkyl compound can be treated by debenzylation as in VI.

6-R ⁷ -substituted-3-azabicyclo [3.1.0] hexane (VIII)

Ethyl diazoacetate was added to N-benzylmaleimide to produce pyrazoline, and then thermally decomposed to 3-benzyl-3-azabicyclo [3.1.0] hexane-2,4-dione-6-carboxylic acid ethyl Get ester. Reduction with lithium aluminum hydride yields 3-benzyl-6-hydroxymethyl-3-azabicyclo [3.1.0] hexane, followed by Swern oxidation followed by oxime formation and aluminum hydride reduction to produce a primary amine. This may be protected or treated as described above to obtain a general formula (VIII) compound wherein R ⁷ is CH ₂ NHCH ₃ or CH ₂ NHCH ₂ CH ₃ .

Alternatively, 3-benzyl-6-hydroxymethyl-3-azabicyclo [3.1.0] hexane can be treated as in VI to yield a 6-methyl derivative. To prepare a compound having a 6-amino group, it is hydrolyzed from 3-benzyl-6-hydroxymethyl-3-azabicyclo [3.1.0] hexane to remove the benzyl group, and then benzyloxycarbonyl group is introduced, At this time, Johnson oxidation results in 3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid. Curtius translocation with diphenylphosphoryl azide as in VIII to give 3-benzyloxycarbonyl-6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane It may take homologues containing primary amines or may be deprotected as in VIII and further treated to give compounds of formula (VIII) wherein R ⁷ is NHCH ₃ or NHC ₂ H ₅ .

Another route for these compounds is 3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-treated by treating N-benzyloxycarbonyl-3-pyrroline with ethyl diazoacetate under rhodium acetate catalysis. Providing ethyl esters of 6-carboxylic acids. Base hydrolysis with sodium hydroxide, for example in methanol, affords the corresponding carboxylic acid, which can be treated as described above. Alternatively, the benzyloxycarbonyl group can be removed by hydrogenolysis, and the nitrogen functionality protected as the benzyl derivative can be removed by treatment with benzyl bromide. Subsequent reduction of aluminum lithium hydride yields 3-benzyl-6-hydroxymethyl-3-azabicyclo [3.1.0] hexane, which can be further penetrated as described above.

1, 2-R ⁶ , R ³ -disubstituted-3-azabicyclo [3.1.0] hexane (IX)

Such substitution forms are obtained by modifying the Oppolzer method described in VII. For 2-methyl substituted compounds, 3-benzylaminobutane nitrile is used as starting material. For all other 2-substituents, 3- (benzylamino) -4-[(tetrahydro-2H-pyran-2) obtainable through carboxylic acid reduction, alcohol protection and N-benzylation from beta-cyano alanine -Yl) oxy] -butannitrile with glycidol to react 3-[(benzyl) (2,3-dihydroxy-propyl) amino] -4-[(tetrahydro-2H-pyran-2-yl) Oxy] butanenitrile can be obtained. Tosylation of the primary alcohol is base-induced ring closure with 3-[(benzyl) (2, 3-epoxypropyl) amino] -4-[(tetrahydro-2H-pyran-2-yl) oxy] -butannitrile Followed by sodium hexamethyldisilazide treatment with 1-benzyl-4-hydroxymethyl-2-[(tetrahydro-2H-pyran-2-yl) oxy] methyl-3-pyrrolidine-carbonitrile Get Secondary tosylation is 3-azabicyclo [3.1.0] hexane of the general formula (IX) in which the 2-substituent is tetrahydropyranyloxymethyl, the 1-substituent is cyano, and the 3-aza nitrogen is benzyl-substituted. May lead to a base-induced-ring closure of The latter nitrile functionality can be converted to all substituents R ⁸ as in VII.

For the refining of the C-2 substituent R ³ , the final C-1 substituent R ⁶ containing the amino group can be protected as the corresponding acetamide. The tetrahydropyran (THP) protecting group is then acid-induced to obtain a primary alcohol, which can be swern-oxidized and the reductive amination of the induced aldehyde with ammonium acetate, methylamine or ethylamine results in R ⁶ CH ₃ or amino-protected CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ NHC ₂ H ₅ , NH ₂ , NHCH ₃ , or NHC ₂ H ₅ , and R ³ is CH ₂ NH ₂ , CH ₂ NHCH ₃ , Or the corresponding amine of formula (IX) which is CH ₂ NHC ₂ H ₅ . The protection of the resulting 2-amines can be done as described above using tert-butoxycarbonyl protecting groups, and the benzyl group is removed via hydrogenation to give the free secondary amine, which is coupled to the quinolone or naphthyridine nucleus. The acetamide and tert-butoxycarbonyl groups can then be acid-derived.

2, 6-R ³ , R ⁷ -disubstituted-3-azabicyclo [3.1.0] hexane (X)

These compounds can be prepared from 3-6-hydroxymethyl-3-azabicyclo [3.1.0] hexane, protected as THP ether and then debenzylated to give 6-[(tetrahydro-2H-pyran-2 -Yl) oxy] methyl-3-azabicyclo [3.1.0] hexane is obtained, followed by introduction of the cyano group to the 2-position by the method of Wood as in VI. Reintroduction of the benzyl group affords 3-benzyl-2-cyano-6-[(tetrahydro-2H-pyran-2-yl) oxy] methyl-3-azabicyclo [3.1.0] hexane and two substituents Is differentially functionalized. The cyano group can convert the desired 2-substituent as described in VI. At this time, protecting any primary amine or secondary amine as its acetamide can lead to acidic removal of the tetrahydropyran protecting group and to scouring the primary alcohol with the desired substituents by the method outlined in VIII.

When the 6-substituent is a methyl group, the refining of the tetrahydropyranyl ether is performed before introducing the cyano group at C-2. If the 2-substituent is a methyl group, another route is to use N-benzyloxycarbonyl-2-methyl-3-pyrroline with rhodium acetate-catalyzed cyclopropane (Takano by Heterocycles, 1989, Possible via the chemical reactions described in 29, 1861, using 4-hydroxy-2-pentene as a starting material). The ester group can then be refined to the desired 6-substituent as in VIII.

1, 4-R ⁹ , R ³ dicyclic-3-azabicyclo [3.1.0] hexane (XI)

These compounds can be prepared from methyl acrylate and 2-benzylamino-3-[(tetrahydro-2H-pyran-2-yl) oxy] propanoic acid methyl ester, and these reagents are heated in methanol to give sodium hexamethyl Additions which can be cyclized to 1-benzyl-4-oxo-5-[(tetrahydro-2H-pyran-2-yl) oxy] methyl] -3-pyrrolidine carboxylic acid methyl ester using disilazide Get water. Reduction and removal of benzyl groups are carried out using raney nickel, followed by introduction of the benzyloxycarbonyl group followed by mesylation of the secondary alcohol, diazabicyclononan-adjusted dehydration to 1-benzyloxycarbonyl-2, 5-dihydro- 5-[(tetrahydro-2H-pyran-2-yl) oxy] methyl-1H-pyrrole-3-carboxylic acid, methyl ester is obtained. According to the method of the synthesis of Dennis et al., 1972, 549, cyclopropane using diiodomethane and zinc / silver pairs, the 1-substituent is CO ₂ CH ₃ and the 4-substituted tetrahydropyranyl A bicyclo [3.1.0] hexyl system of the general formula (XI) in which oxymethyl and 3-nitrogen are protected with benzyloxycarbonyl. The ester can be reduced to the corresponding alcohol where the 1-substituent is hydroxymethyl using lithium borohydride. Subsequently, the benzyloxy carbozyl group was removed by hydrogenolysis using 10% palladium based on carbon, and then benzylated with benzyl bromide to give 1-substituted hydroxymethyl, 4-substituted tetrahydropyranyloxymethyl, A compound of formula (XI) in which 3-nitrogen is protected with benzyl can be obtained. Alternatively, the cyclopropaneated product obtained above can be hydrolyzed with the corresponding acid whose 1-substituent is CO ₂ H using sodium hydroxide. These two compounds can be obtained a 1-substituent R ^9, which are processed as in VIII purpose, after protecting the 1-substituent, tetrahydropyranyl-generate the 4-substituent R ³ as in IX from the protected alcohol You can. Subsequently, removal of 3-benzyloxycarbonyl group can be performed by hydrogenation.

When the desired 4-substituent is a methyl group, the above chemical reaction can be carried out using 2-benzylamino-propanoic acid methyl ester as a starting material.

1, 6-R ⁶ , R ⁷ -disubstituted-3-azabicyclo [3.1.0] hexane (XII)

These compounds can be prepared from tert-butyl acrylate and N-benzylglycine methyl ester, followed by 1-benzyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid, tert butyl ester It is synthesized through the method described in XI. Molybdenum hexacarbonyl-adjusted cyclopropane with ethyl diazoacetate was then used for the 1-substituent to be t-butyloxycarbonyl, the 6-substituent to ethyloxycarbonyl, and 3-nitrogen to benzyloxycarbonyl. The bicyclic system of general formula (XII) is obtained. After selective hydrolysis of the tert-butyl ester with trifluoroacetic acid, the liberated carboxylic acid can be diborane-adjusted and the derived primary alcohol can be protected as its tetrahydro pyranyl ether. The 6-carboethoxy group can then be converted to the desired 6-substituent as described above for the compound of formula (XI). For 6-methyl substituents, the protecting group on nitrogen is changed from benzyloxycarbonyl to benzyl as outlined in IX. After protecting any primary or subamine, the tetrahydropyranyl group can be removed under acidic conditions by the method outlined in VIII, and the primary alcohol can be refined to the desired monosubstituent.

In the case of 1-methyl substituents, N-benzyloxycarbonyl-3-methyl-3-pyrroline (available through N-protection of 3-methyl-3-pyrroline, the preparation of which is Gajda) Liebigs Ann.Chem, 1986, 992) is cyclopropaneized with ethyl diazoacetate under rhodium acetate catalysis to give 1-substituted methyl and 3-substituted benzyloxycarbonyl and 6- Obtain the compound of general formula (XII) whose substituent is ethoxy carbonyl. Subsequently, the ester functional group is refined as described above.

1, 5-R ⁶ , R ⁹ -disubstituted-3-azabicyclo [3.1.0] hexane (XIII)

These compounds are derived from 1-benzyl-4-hydroxymethyl-3-pyrrolidine carbonitrile, the preparation of which is described by Achini and Oppolzer mentioned in VII. After protecting the primary alcohol, 1-benzyl-4-[(tetrahydro-2H-pyran-2-yl) oxy] methyl-3-pyrrolidine carboxylic acid methylester followed by nitrile hydrolysis and diazomethane esterification Get Benzyl groups can be removed by hydrogenation and replaced with benzyloxycarbonyl. Subsequently, introduction of the thiophenyl group was carried out through deprotonation using sodium hydride and reaction of the induced enolate with S-phenyl benzenethiosulfonate, thereby yielding 1-benzyl oxycarbonyl-4-[(tetrahydro-2H-pyran-2 -Yl) oxy] methyl-3-thiophenyl-2-pyrrolidinecarboxylic acid methyl ester can be obtained. Oxidation of sulfur with hydrogen peroxide, followed by pyrolysis of the sulphonated sulfoxide to give alkene 1-benzyloxycarbonyl-2, 5-dihydro-4-[(tetrahydro-2H-pyran-2-yl) oxy] methyl -1H-pyrrole-3-carboxylic acid methyl ester is obtained. Cyclopropaneated with diiodomethane so that the 1-substituted is methoxycarbonyl, the 5-substituted is tetrahydropyranyloxymethyl, and the bicyclic of formula (XIII) substituted with 3-aza benzyloxycarbonyl System is obtained, which can be further refined as in XII to obtain all of the disubstituted compounds.

If the 1-substituent is methyl, the benzyloxycarbonyl group is replaced with a benzyl group as in XI before converting the tetrahydropyranyl oxymethyl group to the methyl group.

2, 4-R ³ , T ¹⁰ -disubstituted 3-azabicyclo [3.1.0] hexane (XIV)

These compounds are prepared from 3-benzyl-2-hydroxymethyl-3-azabicyclo [3.1.0] hexanes according to the method described in X, protecting the primary alcohol as tetrahydropyranyl ether, debenzylating, and It can be prepared by introducing a cyano group at the -position, and then converting it to the desired 2- and 4-substituents.

3-azabicyclo [3.1.0] hexane (XV)

Intia, Attia. 1-benzyl-1, 2, 5, 6-tetrahydropyridine was reacted with diazomethane and zinc iodide according to the method of J. Chem., 16B, 98 (1978) to 3-benzyl-3-azabicyclo [4.1 .0] heptane is obtained. Benzyl groups are removed by hydrogenolysis to yield 3-azabicyclo [4.1.0] heptane.

6-R ⁹ -substituted 3-azabicyclo [4.1.0] heptane ()

3-benzylamino-1,2-dihydroxypropane is reacted with 4-bromobutannitrile to give 4-[(benzyl (2,3-dihydroxypropyl) amino] butannitrile. To obtain 3-benzyl-6-cyano-3-azabicyclo [4.1.0] heptane The nitrile group of this compound can be converted to the desired 6-R ⁹ -substituent as described in VII. .

Alternatively, methyl 1-benzyloxycarbonyl-1, 2, 5, 6-tetrahydropyridine-4-carboxylate is reduced with hydrogenated diisobutylaluminum to yield 1-benzyloxycarbonyl-4-hydroxymethyl- Obtain 1, 2, 5, 6-tetrahydropyridine. Subsequently, cyclopropaneation with samarium amalgam and iodochloromethane yields 3-benzyloxycarbonyl-6-hydroxymethyl-3-azabicyclo [4.1.0] heptane. The hydroxymethyl group can be converted into the desired substituent by the method outlined in VIII.

5-R ⁵ -substituted-3-azabicyclo [4.1.0] heptane (XVII)

These compounds can be prepared from 3-azabicyclo [4.1.0] heptan-4-ones described in US Pat. No. 4,262,124. The reaction of sodium hydride with benzyl bromide yields 3-benzyl-3-azabicyclo [4.1.0] heptan-4-one, which can be treated with a strong base such as lithium hexamethyldisilazide and then reacted with formaldehyde. have. The resulting primary alcohol is then protected as tetrahydro pyranyl ether to give 3-benzyl-5-[(tetrahydro-2H-pyran-2-yl) oxy] methyl-3-azabicyclo [4.1.0] heptan-4 -Get on. Lithium aluminum hydride reduction then yields a bicyclic system of formula (XVII) wherein the 5-substituent is tetrahydropyranyl-protected hydroxymethyl. This substituent can be converted to the desired 5-R ⁵ -substituent by using the method described in VIII after the acid-induced removal of the THP group.

Alternatively, when R ⁵ is amino or substituted amino, the compound may be prepared starting from 1-benzyloxycarbonyl-5-hydroxy-1, 2, 5-6-tetrahydropyridine. Then, samarium-promoted cyclopropane as in XVI, and then benzyloxycarbonyl group is replaced with benzyl as in VIII (benzyl bromide step can be replaced by treatment with benzaldehyde / sodium borohydride) 3-benzyl -5-hydroxy-3-azabicyclo [4.1.0] heptane can be obtained. The corresponding ketone is obtained by Swenn oxidation and subsequent treatment with hydroxylamine hydrochloride, followed by reduction of the lithium hydride of the induced oxime to form 3-benzyl-5-amino-3-azabicyclo [4.1.0] heptane. Get The primary amine can be protected as its tert-butoxycarbonyl derivative, followed by the introduction of N-methyl or N-ethyl groups as necessary in VII.

4-R ³ -substituted-3-azabicyclo [4.1.0] heptane (XVIII)

These compounds can be prepared by protecting the primary alcohol from 2-hydroxymethylpyridine as tetrahydropyranyl ether, followed by Chem. By Sashida and Tsuchiya. Pharm. Bull. 32, 4600 (1984) and reacted with benzyl iodide and sodium borohydride to reduce 1-benzyl-2 [(tetrahydro-2H-pyran-2-yl) oxy] methyl-1, 2, 3, Obtain 6-tetrahydropyridine. Then diazomethane / zinc iodide cyclopropane according to Attia's method in XV to give 3-benzyl-4 [(tetrahydro-2H-pyran-2-yl) oxy] methyl-3-azabicyclo [4.1 .0] heptane is obtained. The tetrahydropyranyl group is then acid-derived by the method described in VIII to obtain the desired 4-R ³ -substituent.

2-R ⁴ -substituted-3-azabicyclo [4.1.0] heptane (XIX)

Compounds of this type are deprotonated from bicyclo [3.1.0] hexan-3-one with strong bases such as lithium hexamethyldisilazide, followed by quenching the induced enolate with formaldehyde and the resulting primary alcohol. Protection as tetrahydropyranyl ether can produce 2-[(tetrahydro-2H-pyran-2-yl) oxy] methyl-bicyclo [3.1.0] hexan-3-one. This compound was subjected to Beckmann translocation through the corresponding oxime tosylate to afford 2-[(tetrahydro-2H-pyran-2-yl) oxy] methyl-3-azabicyclo [4.1.0] heptan-4-one Get Sodium hydride is reacted with benzyl bromide and then reduced with lithium aluminum hydride to yield 3-benzyl-2-[(tetrahydro-2H-pyran-2-yl) oxy] methyl-3-azabicyclo [4.1.0] heptane. Obtained, the protected hydroxymethyl 2-substituents can be converted to the desired 2-substituents using the method described in IX.

1-R ⁶ -substituted-3-azabicyclo [4.1.0] heptane (XX)

These compounds are prepared from methyl 1-benzyloxycarbonyl-1, 2, 5, 6-tetrahydropyridine-3-carboxylate, and 3-benzyloxycarbonyl-1-hydroxy by using the method described in XVI. Methyl-3-azabicyclo [4.1.0] heptane can be produced. The method described in VIII can be used to convert hydroxymethyl groups to the desired substituents. In this case, and in another case using Curtius potential, the Overman Org. Synth. Coll. Good results can be obtained using the modified Curtis reaction described in Volume VI, 95.

7-R ⁷ -substituted-3-azabicyclo [4.1.0] heptane (XXI)

These compounds were reacted with ethyl diazoacetate from 1-benzyl-5, 6-dihydro-2 (1H) -pyridinone with a molybdenum hexacarbonyl catalyst to yield 3-benzyl-2-oxo-3-azabicyclo [4.1 .0] heptan-7-carboxylic acid ethyl ester can be obtained, which is reduced to lithium aluminum hydride to yield 3-benzyl-7-hydroxymethyl-3-azabicyclo [4.1.0] heptane. The desired 7-R ⁷ -substituent is then obtained using the method of VIII.

Alternatively, 1-benzyloxycarbonyl-1, 2, 5, 6-tetrahydropyridine is reacted with ethyl diazoacetate under rhodium acetate catalysis to yield ethyl-3-benzyloxycarbonyl-3-azabicyclo [4.1. 0] heptan-7-carboxylate can be obtained. Subsequently, ester hydrolysis with sodium hydroxide gives the corresponding carboxylic acid, which can be converted as described in VIII to yield amino or substituted amino derivatives.

2,7-R ⁴ , R ⁷ -disubstituted-3-azabicyclo [4.1.0] heptane (XXIII)

These compounds are derived from 1-methyl-2-tetrahydropyranyloxymethyl-1,2,5,6-tetrahydropyridine, which are prepared from 2- (hydroxymethyl) pyridine using the method outlined in XVIII. can do. Treatment of 1-methyl-2-tetrahydropyranyloxymethyl-1,2,5,6-tetrahydropyridine with α-chloroethyl chloroformate, followed by methanol to remove the 1-methyl group, followed by benzyl chloro Treatment with formate yields 1-benzyloxycarbonyl-2-tetrahydropyranyloxymethyl-1,2,5,6-tetrahydropyridine. The compound was cyclopropaneated with ethyl diazoacetate in the presence of a catalytic amount of rhodium acetate to give ethyl 3-benzyloxycarbonyl-2-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptan-7-carboxyl Get rate. This can be converted to the compound with the desired substitution form using the chemical reaction described in XI.

2,6-R ⁴ , R ⁹ -disubstituted-3-azabicyclo [4.1.0] heptane (XXIV)

These compounds can be prepared from methyl 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-carboxylate. Deprotonated with a strong base such as lithium diisopropylamide or lithium hexamethyldisilazide, then reacted with formaldehyde and the resulting primary alcohol protected as its tetrahydropyranyl derivative to methyl 1-benzyloxycarbonyl-2 -Tetrahydropyranyloxy methyl-1,2,5,6-tetrahydropyridine-4-carboxylate can be obtained. This compound is treated using the method described in XVI to yield 3-benzyloxycarbonyl-6-hydroxymethyl-2-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptane, which is VIII. And the chemical reaction in XI can be converted to the desired disubstituted compound.

1,7-R ⁶ , R ⁷ -disubstituted-3-azabicyclo [4.1.0] heptane (XXVII)

Methyl 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate is reduced to diisobutylaluminum hydride and the resulting primary alcohol is protected as its tetrahydropyranyl derivative. Can be. Then cyclopropaneated with ethyl diazoacetate in the presence of rhodium acetate to give ethyl ester of 3-benzyloxycarbonyl-1-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptan-7-carboxylic acid. Get This compound is treated as in XII to obtain the desired substitution.

Alternatively, tert-butyl 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate is cyclopropaneated using ethyl diazo acetate to catalyze hexacarbonyl molybdenum 1 -tert-butyl-7-ethyl 3-benzyloxycarbonyl-3-azabicyclo [4.1.0] heptane-1,7-dicarboxylic acid can be obtained. The chemistry described in XII can be applied and used to synthesize the desired disubstituted compound.

1,6-R ^6, R ⁹ - disubstituted-3-azabicyclo [4.1.0] heptane (XIVII)

Benzylamine was added to 1-tetrahydropyranyloxy-3-buten-2-one, followed by Witig olefination of the ketone with methyltriphenylphosphonium bromide and a base to 4-benzylamino-2- Methylene-1- (tetrahydropyranyloxy) butane is obtained. Subsequently, monoethylmalonate and amide are produced using carbonyldiimidazole as a condensing agent to obtain a dicarbonyl compound, which is either p-toluenesulfonyl azide or p-carboxy under the influence of t-butoxylated potassium or potassium hydride. Diazo transfer using phenylsulfonyl azide. Alternatively, Koskinen's J. Chem. Soc. Chem. Commun., 1990, 652 may be used. The resulting diazo compound was converted to Chem. Pharm. The ethyl ester is obtained by treatment with rhodium acetate in refluxing benzene according to the method of Bull., 1985, 61. Lithium aluminum hydride is reduced to obtain a compound of formula (XXVIII) wherein the 1-substituent is hydroxymethyl and the 6-substituent is tetrahydropyranyloxymethyl. This compound can be treated with the desired side chain by the chemical reactions described in XI and VIII.

1,5-R ⁶ , R ⁵ -disubstituted-3-azabicyclo [4.1.0] heptane (XXIX)

2-ethenyl-1,3-propanediol was synthesized by Syn. It may be prepared using the method of Commun., 1986, 261. After sun protection as the tetrahydropyranyl derivative, the remaining primary alcohol can be mesylated and substituted with benzylamine to give 4- (benzylamino) -3-tetrahydropyranyloxymethyl-1-butene. Amide formation with monoethylmalonate as in XXVII, diazo transfer, and then cyclization to 3-benzyl-2-oxo-5-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptane- Obtain ethyl ester of 1-carboxylic acid. Lithium aluminum hydride reduction yields 3-benzyl-1-hydroxymethyl-5-tetrahydro pyranyloxymethyl-3-azabicyclo [4.1.0] heptane, using the chemical reactions outlined in XI and VIII to It can be converted into a substituent.

5,7-R ⁵ , R ⁷ -disubstituted-3-azabicyclo [4.1.0] heptane (XXXII)

5-tetrahydropyranyloxy-1,3-pentadiene by cyclo addition of benzyl ester of methylenecarbamic acid to 1-benzyloxycarbonyl-3-tetrahydropyranyloxy methyl-1,2,3,6-tetra Obtain hydropyridine. Subsequently, cyclopropaneated with ethyldiazo acetate and rhodium acetate to give ethyl ester of 3-benzyloxycarbonyl-5-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptan-7-carboxylic acid. Get Subsequently, the conversion to the desired disubstituted compound can be carried out as described in XII.

5,6-R ⁶ , R ⁹ -disubstituted-3-azabicyclo [4.1.0] heptane (XXXIV)

After allylamine is added to ethyl 4-chloroacetoacetate, the resulting secondary amine is protected as its benzyloxycarbonyl derivative to give ethyl N-aryl-N-benzyloxycarbonyl-4-amino-3-oxo-butanoic acid. Get Diazo transfer and then rhodium-adjusted cyclization as described in XXVIII can yield ethyl 3-benzyloxycarbonyl-5-oxo-3-azabicyclo [4.1.0] heptan-6-carboxylate. have. Olefinized with (methoxymethyl) triphenylphosphonium chloride and base, followed by mild acid hydrolysis to ethyl 3-benzyloxycarbonyl-5-carboxaldehyde-3-azabicyclo [4.1.0] heptan-6 -Carboxylate is obtained. Oxidation of aldehydes to carboxylic acids can be carried out using sodium chlorite or tetra-n-butylammonium permanganate. The product of formula (XXXIV) wherein R ⁵ is carboxylic acid and R ⁹ is ethyl ester can be converted to the desired disubstituted compound using the method outlined in XII.

6,6-R _ω , R ²⁵ -disubstituted-3-azabicyclo [3.1.0] hexane (XXXVII)

These compounds are derived from methyl tert-butyl 3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-6,6-dicarboxylic acid, which is obtained from the method of Synthesis, Ohishi, 1980, 690 or It can be prepared by cyclopropane 1-benzyloxycarbonyl-3-pyrroline using the methods of Synthesis, 1973, 137 by Peace and Wolfman. Removal of the tert-butyl ester can be done by a simple treatment with trifluoroacetic acid, and the free carboxylic acid is then carried out by the method of Baldwin, J. Chem. Soc. Chem. Commun., 1988, 775 can be converted to amino groups. The resulting compound of formula (XXXVII), wherein the 3-substituent is benzyloxycarbonyl and the 6-substituent is amino and methoxycarbonyl, can then be protected with its tert-butoxycarbonyl derivative, as in VII. The amines can be alkylated to yield N-methyl and N-ethyl derivatives. The ester functional group can be reduced with lithium borohydride to give a primary alcohol which can be treated as in IX to yield an aminomethyl substituent.

If at least one of the 6-substituents is methyl, the tert-butyl ester is deprotected to reduce the resulting carboxylic acid to diborane so that the 3-substituent is benzyloxycarbonyl and the 6-substituents are hydroxymethyl and methoxy Obtain the compound of the general formula (XXXVII) which is carbonyl. The benzyloxycarbonyl group is replaced with the benzyl group as in XI, followed by tosylation of the alcohol. Reduction with lithium aluminum hydride yields a compound of formula (XXXVII) wherein the 3-substituent is benzyl and the 6-substituent is methyl and hydroxymethyl. The hydroxymethyl group can be converted into the desired substituent by the method outlined in VIII.

Or in the alternative, to produce compounds wherein at least one of the 6-substituents is methyl. Chem., 1976, 2965 can be used. Thus, 1-benzyloxycarbonyl-3-pyrroline can be reacted with dibromocarbene to obtain 3-benzyloxycarbonyl-6,6-dibromo-3-azabicyclo [3.1.0] hexane. have. One of the bromine is replaced by methyl using n-butyllithium and methyl iodide. The resulting compound was again metal-halogen exchanged using butyllithium at low temperature and the anion was quenched with formaldehyde to give 3-benzyl-6-hydroxymethyl-6-methyl-3-azabicyclo [3.1.0] hexane. Get The production of initial gem-dibromo cyclopropane can also be done using phenyl (tribromomethyl) mercury. The hydroxymethyl group can be converted into the desired substituent by the method outlined in VIII.

To produce a compound in which the 6-substituents are both aminomethyl derivatives, methyl tert-butyl 3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-6,6-dicarboxylic acid was converted to trifluoroacetic acid. Deprotect once more. The free carboxylic acid is condensed with ammonia, methylamine or ethylamine using an active agent such as dicyclohexylcarbodiimide or carbonyldiimidazole to produce the corresponding amide. The methyl ester is then hydrolyzed to N-carboxylic acid under acidic or basic conditions and another amide is produced in a similar manner. The resulting compound of formula (XXXVII), wherein the two 6-substituents are amides optionally substituted with methyl or ethyl groups, is then converted from the N-benzyloxycarbonyl derivative to the N-benzyl compound as in XI. Subsequent reduction with lithium aluminum hydride yields a compound containing two aminomethyl groups optionally substituted at the 6-position with methyl or ethyl groups. Protected as a di-tert-butoxycarbonyl derivative and removal of the benzyl group by hydrolysis yields a compound in a form suitable for coupling to compound II.

1,2,6-R ⁶ , R ³ , R ⁷ -trisubstituted-3-azabicyclo [3.1.0] hexane (XXXVIII)

A. R ⁷ is methyl

These compounds are derived from 1-benzylamino-2-butene which can be obtained from the reaction of benzylamine with 1-bromo-2-butene. As in XXVIII, 3-benzyl-6-methyl-2-oxo-3-azabicyclo [3.1.0] hexane- was subjected to amide formation using monoethyl malonate, diazo transition and cyclization using rhodium acetate. Obtain 1-carboxylic acid ethyl ester. After reduction with lithium borohydride, the resulting hydroxymethyl group is protected as its tetrahydropyranyl ether, whereby R ³ is a double bond to oxygen, R ⁶ is a tetrahydropyranyloxy methyl group, and R ⁷ is a methyl group. Obtain the compound of formula (XXXVIII). The compound was treated with methyllithium followed by sodium borocyanohydride according to Shigagaki's study, Heterocycles, 1986, 423 to benzyl-2,6-dimethyl-1-tetrahydropyranyloxymethyl- Obtain 3-azabicyclo [3.1.0] hexane, where the 1-substituents are aligned as in X to afford compounds of formula (XXVII) wherein R ³ and R ⁷ are methyl groups.

Alternatively, the amide functionality in the 1-tetrahydropyranyloxymethyl compound can be reduced to carbinolamine using hydrogenated bis (2-methoxy ethoxy) aluminum sodium (Red-Al) at -78 ° C. The alcohol functional group is methylated with methyl iodide and then replaced with trimethylsilylcyanide to give a compound of formula (XXXVIII) wherein R ³ is cyano, R ⁶ is tetrahydropyranyloxymethyl and R ⁷ is methyl. At this time, the cyano group can be converted into the desired substituent by the method outlined in VI. The 1-substituent is converted from the tetrahydropyranyloxymethyl substituent by the chemical reaction described in IX or X.

B. R ⁶ is methyl

Reacting 3-methyl-1,4-pentadiene with less than 1 equivalent of osmium tetraoxide to give a diol, which is monoprotected in primary alcohols, yields 2-hydroxy-3-methyl-1-tetrahydropyranyloxy-4- Pentene can be obtained. This compound is treated by the chemical reaction described in Takano's Heterocycles 1989, 1861 to give 1-benzyloxycarbonyl-3-methyl-2-tetrahydropyranyloxymethyl-3-pyrroline. Cyclopropane using ethyl diazoacetate under rhodium acetate catalysis to obtain a compound of formula (XXXVIII) wherein R ³ is tetrahydropyranyloxymethyl, R ⁶ is methyl and R ⁷ is ethoxycarbonyl . Hydrolysis of the ethyl ester under basic conditions yields the carboxylic acid as a 6-substituent, which can be converted to an amine or alkylated amine using the chemical reaction described in VIII. Alternatively, the benzyloxycarbonyl group can be substituted with a benzyl group as in XI and the ester group can be converted to a (alkyl) amino methyl group as in VIII. After protecting any amine group at the 6-position, the tetrahydropyranyloxymethyl group can be converted to the desired substituent using the chemistry of IX or X.

If both 1- and 6-substituents are methyl, the same chemical reaction can be carried out using 1-benzyloxycarbonyl-2,3-dimethyl-3-pyrroline as starting material.

C. R ³ is methyl

In this case, the starting material is 1-benzyloxycarbonyl-2-methyl-3-pyrroline-3-carboxyl obtained from the chemical reaction of XII using tert-butyl crotonate instead of tert-butyl acrylate. Tert-butyl ester of acid. Cyclopropaneation with ethyl diazoacetate as described above affords a compound of formula (XXXVIII) wherein R ³ is methyl, R ⁶ is tert-butoxycarbonyl and R ⁷ is ethoxycarbonyl. Trifluoroacetic acid can be used to hydrolyze tert-butyl ester, followed by Curtius transposition with diphenyl phosphoryl azide in tert-butanol to obtain protected 1-amino substituents, which is necessary If alkylated as in VIII. Alternatively, the acid mother nucleus in the 1-position can be reduced with diborane to yield hydroxymethyl substituents, which can be refined as in VIII or IX. The ethyl ester is then hydrolyzed under basic conditions at the 6-position, and the resulting acid is then subjected to a similar Curtius potential and further refined or reduced to a hydroxymethyl group using lithium borohydride. The hydroxymethyl group can then be converted to the desired substituent by the chemical reaction described in IX.

1,6,6-R ⁶ , R ⁷ , R ²⁵ -trisubstituted-3-azabicyclo [3.1.0] hexane (XL I)

A. R ⁶ is methyl

These compounds can be prepared by cyclopropane using tert-butylmethyl malonate or diazo derivatives thereof, as outlined in XXXVII from 1-benzyloxycarbonyl-3-methyl-3-pyrroline. The resulting tert-butylmethyl 3-benzyloxycarbonyl-1-methyl-3-azabicyclo [3.1.0] hexane-6,6-dicarboxylic acid can be further functionalized as described in XXXVII.

B. R ⁷ is methyl

Compounds of this kind are derived from 1-benzyloxycarbonyl-3-tetrahydropyranyloxymethyl-3-pyrroline. This starting material may be prepared by deprotonation from 1-benzyloxycarbonyl-3-pyrrolidinone with a strong base such as lithium hexamethyldisilazide and then quenched with formaldehyde. The free alcohol is protected as its tetrahydropyranyl derivative and the ketone is reduced with sodium borohydride. The resulting alcohol is dehydrated in pyridine with phosphorus oxychloride to give the essential starting material.

Ethyl of 3-benzyloxycarbonyl-1-tetrahydropyranyloxymethyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid by cyclopropane using ethyl diazoacetate under rhodium acetate catalysis An ester is obtained, which can be deprotonated using a strong base such as potassium hydride or lithium hexamethyldisilazide and methylated at the 6-position by reacting the induced enolate with methyl iodide. The ester is then hydrolyzed in methanol with sodium hydroxide and the resulting carboxylic acid is then functionalized as desired using the method described in XI or XXXVII (C).

Alternatively, the pyrroline starting material is cyclo propaneized as in XXXVI to give t-butyl methyl 3-benzyloxycarbonyl-1-tetrahydropyranyloxymethyl-3-azabicyclo [3.1.0] hexane-6,6 -Dicarboxylic acid can be obtained. This can be generated by treatment as in XXXVII. Subsequently, the desired substitution is obtained using the chemistry outlined in XI.

1,5,6-R ⁶ , R ⁹ , R ⁷ -trisubstituted-3-azabicyclo [3.1.0] hexane (XLII)

A. R ⁷ is methyl

The 1-bromo-2-tetrahydropyranyloxymethyl-2-butene can be reacted with benzylamine and then the resulting secondary amine can be condensed with the monoethyl ester of the malone ester as described in XXXVII. Diazo transfer and intramolecular cyclopropane as described in XXXVII to give ethyl 3-benzyl-6-methyl-2-oxo-5-tetrahydropyranyloxymethyl-3-azabicyclo [3.1.0] hexane-1 Obtain carboxylic acid. Lithium hydride is reduced to obtain a compound of formula (XLII) wherein the 1-substituent is hydroxymethyl, the 5-substituent is tetrahydropyranyloxymethyl, and the 6-substituent is methyl. This compound can be made into the desired side chain using the chemical reactions described in XI and VIII.

B. R ⁶ is methyl

These compounds are derived from 1-chloro-2-methyl-4-tetrahydropyranyloxy-2-butene, the preparation of which is based on Schmid's Helv. Chim. Acta, 1982, 684. This compound is treated as in A above to obtain 3-benzyl-1-hydroxymethyl-5-methyl-60tetrahydropyranyloxymethyl-3-azabicyclo [3.1.0] hexane. This compound can also be converted to the desired side chain using the chemical reactions described in XI and VIII.

2,4,6-R ³ , R ¹⁰ , R ⁷ -trisubstituted-azabicyclo [3.1.0] hexane (XLV)

A. R ⁷ is methyl

3-benzyl-6-methyl-3-azabicyclo [3.1.0] hexane (its method outlined in VIII) for the preparation of this kind of compound was prepared by the method described in X. Convert to no-6-methyl-3-azabicyclo [3.1.0] hexane. The nitrile can then be hydrolyzed under acid or base conditions and then lithium aluminum hydride reduced and the resulting primary alcohol protected in its tetrahydropyranyl derivative. Further functionalization is carried out as in XIV to obtain the desired substitution form.

B. R ³ is methyl

These compounds are derived from 1-benzyloxycarbonyl-2-methyl-3-pyrroline. As described for X, cyclopropaneated with ethyl diazoacetate, followed by ester reduction with lithium borohydride, and the resulting primary alcohol protected as its tetrahydropyranyl derivative to 3-benzyloxycarbonyl-2-methyl -6-tetrahydropyranyloxymethyl-3-azabicyclo [3.1.0] hexane is obtained. Subsequently, the benzyloxycarbonyl group may be removed by hydrogenolysis, and then a cyano group may be introduced at the 4-position. Tri-substituted 3-azabicyclo [3.1] obtained by the method outlined in X for 4-cyano-2-methyl-6-tetrahydropyranyloxymethyl-3-azabicyclo [3.1.0] hexane obtained by this method .0] hexane.

1,2,7-R ⁶ , R ⁴ , R ⁷ -trisubstituted-3-azabicyclo [4.1.0] hexane (XLVI)

A. R ⁷ is methyl

Benzylamine and 5-bromopent-2-ene are reacted to give 5-benzylamino-2-pentene, which can be condensed with the half-ester of malonic acid as described in XXVII. Then, according to XXVII, diazo transfer is carried out and cyclo is added to give ethyl-3-benzyloxycarbonyl-7-methyl-2-oxo-3-azabicyclo [4.1.0] hexane-1-carboxylate. This compound is treated as in XXXVII to afford the desired trisubstituted compound.

B. R ⁶ is methyl

Benzyl ester of methylenecarbamic acid is cycloadded to 3-methyl-5-tetrahydropyranyloxy-1,3-pentadiene to yield 1-benzyloxycarbonyl-3-methyl-2-tetra hydropyranyloxymethyl-1 Obtain 2,5,6-tetrahydropyridine. Subsequently, cyclopropaneation with ethyl diazoacetate as described above yields a compound of the general formula (XLVI) wherein R ⁷ is ethyl ester, R ⁶ is methyl and R ⁴ is tetrahydropyranyloxymethyl. This compound can be converted to the desired trisubstituted side chain using the method described in XI.

C. R ⁴ is methyl

Benzyl ester of methylenecarbamic acid is cycloadded to 3-tetrahydropyranyloxymethyl-1,3-pentadiene to give 1-benzyloxycarbonyl-2-methyl-3-tetra hydropyranyloxymethyl-1,2, Obtain 5,6-tetrahydropyridine. Cyclopropaneation with ethyl diazoacetate gives a compound of the general formula (XLVI) wherein R ⁷ is an ethyl ester group, R ⁶ is tetrahydropyranyloxymethyl and R ⁴ is methyl. The chemical reaction described in XII can be used to convert this compound into the desired side chain.

2,7,7-R ⁴ , R ⁷ , R ²⁵ -trisubstituted-3-azabicyclo [4.1.0] heptane (L)

A. R ⁴ is methyl

Benzyl ester of methylenecarbamic acid is cycloadded to 1,3-pentadiene to give 1-benzyloxycarbonyl-2-methyl-1,2,5,6-tetrahydropyridine. Subsequently, tert-butyl methyl malonate or a diazo derivative thereof is cyclopropane as outlined in XXXVII, where R ⁴ is a methyl group, R ⁷ is a methyl ester group, and R ²⁵ is a tert-butyl ester group (L To a compound. This compound is then converted using the chemical reaction outlined in XXXVII.

B. R ⁷ is methyl

1-benzyloxycarbonyl-2-tetrahydropyranyloxymethyl-1,2,5,6-tetrahydropyridine was reacted with bromoform under basic conditions as in XXXVII to give 3-benzyloxycarbonyl-7, 7-Dibromo-2-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptane is obtained, which can be further converted to the desired compound using the method described in XXXVII.

1,6,7-R ⁶ , R ⁹ , R ⁷ -trisubstituted-3-azabicyclo [4.1.0] heptane (LVIII)

A. R ⁷ is methyl

Benzylamine was added to 1-tetrahydropyranyloxy-3-buten-2-one, followed by wittig olefination of the ketone with ethylidene triphenylphosphoran, to yield 5-benzylamino-3-tetrahydro Obtain pyranyloxymethyl-2-pentene. Amide production using monoethyl malonate, followed by diazo transfer and rhodium-catalyzed cyclo addition, as described in XXXVII, for 3-benzyl-7-methyl-2-oxo-6-tetrahydropyranyloxymethyl-3 Ethyl esters of azabicyclo [4.1.0] heptane-1-carboxyl can be obtained. This compound can be further treated as in XXXVII.

B. R ⁹ is methyl

Benzylamine is added to methyl vinyl ketone and then the ketone is olefinated using ethyl 2-trimethylsilyl acetate and base to obtain unsaturated esters, which can be reduced to hydrogenated diisobutylaluminum. The resulting primary alcohol is protected with its tetrahydropyranyloxy derivative to give tetrahydropyranyl protective 5-benzylamino-3-methyl-pent-2-en-1-ol. Amides are then produced as described in XXVII and cyclo-added to 3-benzyl-6-methyl-2-oxo-7-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptan-1-car Obtain ethyl ester of acid. This can be treated with the desired derivative using the chemistry outlined in XXVII.

C. R ⁶ is methyl

Benzylamine was added to 1-tert-butyldimethylsilyloxy-3-buten-2-one, and then Peterson olefins were used to ethylen triethylsilylacetate and base to yield unsaturated esters, which It can be reduced to hydrogenated diisobutyl aluminum. The resulting primary alcohol can be protected as its tetrahydro pyranyloxy derivative. As described in XXVII, amide formation, cyclo addition, and lithium aluminum hydride reduction resulted in 3-benzyl-6-tert-butyldimethylsilyloxymethyl-1-hydroxymethyl-7-tetrahydropyranyl oxymethyl- Obtain 3-azabicyclo [4.1.0] heptane. The reduction of the primary alcohol to the methyl group at 1 position can be carried out using the method described in VI. Subsequently, the removal of the tert-butyldimethylsilyl protecting group at the 6 position can be performed using tetra-n-butyl ammonium fluoride in tetrahydrofuran solution. The resulting 3-benzyl-6-hydroxymethyl-1-methyl-7-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptane was converted to the desired compound using the chemistry in XI and VIII. You can.

4,5,7-R ³ , R ⁵ , R ⁷ -trisubstituted-3-azabicyclo [4.1.0] heptane (LXX)

A. R ³ is methyl

1-benzyloxycarbonyl-1,6-dihydro-3 (2H) -pyridinone was cyclopropaneated with ethyl diazoacetate under hexacarbonyl molybdenum action to yield 3-benzyloxycarbonyl-5-oxo-3 Ethyl ester of azabicyclo [4.1.0] heptan-7-carboxylic acid can be obtained. This compound is treated with a base such as lithium hexamethyldisilazide or potassium tert-butoxide followed by methyl iodide to introduce the methyl group at the 4-position. This compound is wittig reacted as in XXXIV and further processed to give the desired trisubstituted compound.

B. R ⁵ is methyl

Ethyl ester of 3-benzyloxycarbonyl-5-oxo-3-azabicyclo [4.1.0] heptan-7-carboxylic acid using a strong base such as lithium hexamethyldisilazide or potassium tert-butoxide The oleate can then be quenched to formaldehyde to obtain a primary alcohol, which can be protected by its tetrahydropyranyloxy derivative. The resulting ethyl 3-benzyloxycarbonyl-5-oxo-4-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptan-7-carboxylate is olefin with base and methyltriphenyl phosphonium bromide Mad. Hydrogenation of the double bond under the catalyst followed by reintroduction of the benzyloxycarbonyl group resulted in 3-benzyloxycarbonyl-5-methyl-4-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptan-7- Obtain ethyl ester of carboxylic acid, which can be further refined as in XI.

C. R ⁷ is methyl

1-benzyloxycarbonyl-5-hydroxy-1,2,5,6-tetrahydropyridine was prepared using 3-benzyloxycarbonyl-7-bromo-7-methyl-5- using the method described in XXXVII. It can be converted to hydroxy-3-azabicyclo [4.1.0] heptane. It is then reacted with hydrogenated tri- (n-butyl) tin to give a debrominated compound. The alcohol is oxidized to a ketone using pyrochromium pyridinium or Swern oxidation to give 3-benzyloxycarbonyl-7-methyl-5-oxo-3-azabicyclo [4.1.0] heptane. As described in B above, deprotonation, formaldehyde quenching, and then protected as tetrahydropyranyloxy derivatives resulted in 3-benzyloxycarbonyl-7-methyl-5-oxo-4-tetrahydropyranyloxy Obtain methyl-3-azabicyclo [4.1.0] heptane. The conversion of the ketone to the cognate carboxylic acid can be done as described in XXXIV. The resulting 3-benzyloxycarbonyl-7-methyl-4-tetrahydropyranyloxymethyl-3-azabicyclo [4.1.0] heptan-5-carboxylic acid is converted as in XI to obtain the desired substituents.

Pharmaceutically acceptable acid addition salts of compound (I) are prepared by conventional methods by treating a solution or suspension of free base (I) with about 1 chemical equivalent of pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are used to isolate the salts. Examples of suitable acids include acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfonic acid Palmic acid and sulfonic acid.

Pharmaceutically acceptable cationic salts of compound (I) can be prepared from the corresponding acids by conventional means, for example by reaction with about 1 equimolar amount of base. These cationic salts do not increase the toxicity of the compound to animal organisms. Examples of suitable cationic salts are cations of alkali metals such as sodium or potassium, alkaline earth metals such as magnesium or calcium and organic amines such as ammonium or diethanolamine or N-methylglucamine.

The novel compounds of formula (I) and their pharmaceutically acceptable acid addition salts are useful for the treatment of a wide range of bacterial infections, in particular for the treatment of Gram-positive bacterial strains.

The compounds of the present invention may be administered alone, but generally in the manner of administration and standard pharmaceutical practice, may be administered with a selected pharmaceutical carrier. For example, the compound may be administered orally or in the form of a tablet containing an excipient such as starch or lactose, alone or in a capsule mixed with an excipient, or of an elixir or suspending agent containing a flavoring or coloring agent. Can be administered in the form. For animals, this compound is advantageously contained in animal feed or beverages at a concentration of 5-5000 ppm, preferably 25-500 ppm. This compound can be injected parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral administration, the compound is most preferably used in the form of a sterile aqueous solution which may contain sufficient salt or glucose to make other solutes, for example, solutions, isotonic. In the case of animals, the compound is administered at a dose of about 0.1-50 mg / kg / day, advantageously at a dose of 0.2-10 mg / kg day provided in a single daily dose or up to three divided doses It can be administered intramuscularly or subcutaneously.

The present invention also obtains a pharmaceutical composition consisting of an antimicrobially effective amount of a compound of formula (I) together with a pharmaceutically acceptable diluent or carrier.

The compounds of the present invention can be administered orally or parenterally to humans for the treatment of bacterial diseases, at dosage levels of about 0.1 to 500 mg / kg day, advantageously in single doses or up to three divided doses. It may be administered orally at a dosage level of 0.5-50 mg / kg / day provided in a dose. For intramuscular or intravenous administration, the dosage level is about 0.1-200 mg / kg / day, advantageously 0.5-50 mg / kg / day. Intramuscular administration can be a single dose or up to three divided doses, and intravenous administration can be continuous dropping administration. It may be necessary to vary according to the weight and condition of the patient being treated and the particular mode of administration chosen is known to those skilled in the art.

The antimicrobial activity of the compounds of this invention is E. coli. E. Steers et al., By testing according to Steer's replicator technique, a standard in vitro bacterial test method described in Antibiotics and Chemotherapy, 9,307 (1959).

In the following preparations and examples, the temperature is expressed in degrees Celsius.

Production Example A

1.N-benzyl-N- (2-cyanoethyl) -3-amino-1,2-propanediol

A solution of glycidol (25.4 ml, 0.383 mol) and 3- (benzylamino) propionitrile (50 ml, 0.319 mol) in ethanol (383 ml) was heated to reflux for 65 hours. The solvent was removed under reduced pressure to give a yellow oil which was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated sodium chloride solution and then dried over sodium sulfate. Filtration and concentration in vacuo gave an oil (75 g) which was purified by column chromatography (eluant: 5% methanol in chloroform) to give the title product (55.3 g, 0.236 moles, 74% yield) as a colorless oil.

¹ H NMR (CDCl ₃ ): 7.35 (m, 5H), 3.86 (d, J = 13Hz, 1H), 3.8 (m, 2H), 3.64 (d, J = 13Hz, 1H), 3.53 (dd, J = 13 Hz, 1H), 3.20 (bs, 1H), 2.95 (m, 1H), 2.84 (m, 1H), 2.75 (dd, J = 12.8 Hz, 1H), 2.63 (dd, J = 13.4 Hz, 1H), 2.50 (m, 2 H).

2.N-benzyl-N- (2-cyanoethyl) -3-amino-1,2-bis (methanesulfonyloxy) propane

A solution of the title compound (11.2 g, 47.8 mmol) and triethylamine (8.14 ml, 105 mmol) in Preparation Example A.1. In methylene chloride (480 ml) was cooled to 10 ° C. and methanesulfonyl chloride (16.6 ml, 119 mmol). After 85 minutes at −10 ° C., the reaction mixture was poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted twice with methylene chloride and then the combined organic layers were dried over magnesium sulfate. Filter and remove the solvent in vacuo to yield the title product (18.0 g, 47.6 mmol, yield 99%) as a yellow oil, which was used without purification.

¹ H NMR (CDCl ₃ ): 7.31 (m, 5H), 4.75 (m, 1H), 4.55 (dd, J = 12.3 Hz, 1H), 4.27 (dd, J = 12.6 Hz, 1H), 3.68 (Company AB) Midline, J = 12 Hz, 2H), 3.07 (s, 3H), 3.02 (s, 3H), 2.88 (m, 4H), 2.48 (m, 2H).

3. 3-benzyl-1-cyano-3-azabicyclo [3.1.0] hexane

N-benzyl-N- (2-cyanoethyl) -2,3-dimethanesulfonylpropylamine (32.25 g, 85.2 mmol) was dissolved in benzine (800 ml), cooled to -10 ° C and then sodium hexa Treatment with methyldisilazide (170 ml of 1 M solution in tetrahydrofuran, 170 mmol). After 2 hours, the reaction mixture was quenched with saturated ammonium chloride solution and then the mixture was extracted three times with methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered and then concentrated in vacuo. Chromatographic purification (eluent; 4: 1 = hexane: ethyl acetate) gave the title product as a yellow oil (8.23 g, 41.5 mmol, 49% yield).

¹ H NMR (CDCl ₃ ): 7.26 (m, 5H), 3.59 (s, 2H), 3.11 (d, J = 9 Hz, 1H), 2.94 (d, J = 9 Hz, 1H), 2.54 (d, J = 9 Hz, 1H), 2.47 (dd, J = 10.4 Hz, 1H), 2.03 (m, 1H), 1.57 (m, 1H), 1.10 (dd, J = 8.5 Hz, 1H).

4. 1-Aminomethyl-3-benzyl-azabicyclo [3.1.0] hexane

Lithium aluminum hydride (70 ml of 1M solution in diethyl ether, 70 mmol) in 3-benzyl-1-cyano-3-azabicyclo [3.1.0] hexane (3.35 g, 16.9 mmol) in tetrahydrofuran (200 ml) Was added to the solution. After 18 h at rt, the reaction mixture was treated sequentially with water (2.6 ml), sodium hydroxide (2.6 ml 15% aqueous solution) and water (7.8 ml). The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title product (3.47 g, yield 100%) as a pale yellow black oil, which was used without purification.

¹ H NMR (CDCl ₃ ): 7.20 (m, 5H), 3.54 (AB quartet, J = 12 Hz, 2H), 2.92 (d, J = 8 Hz, 1H), 2.87 (d, J = 9 Hz, 1H), 2.81 (d, J = 13 Hz, 1H), 2.59 (d, J = 13 Hz, 1H), 2.33 (dd, J = 8.4 Hz, 1H), 2.25 (d, J = 7 Hz, 1H), 1.10 (m, 1H ), 0.97 (m, 1H), 0.30 (dd, J = 8.5 Hz, 1H).

5. 3-benzyl-1- [N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hexane

A solution of the title compound (2.19 g, 10.8 mmol) and triethylamine (1.8 mL, 13 mmol) in Preparation A.4. In water-soluble dioxane (8.8 ml of water and 80 ml of dioxane) was prepared by di-tert-butyl bicarbonate ( 2.6 g, 11.9 mmol). After 1 hour at room temperature, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a viscous pale yellow oil. Purification by column chromatography (eluent: 95: 5: 0.5 chloroform: methanol: concentrated ammonium hydroxide) afforded the title product as a colorless oil (3.27 g, 10.8 mmol, 100% yield).

¹ H NMR (CDCl ₃ ): 7.26 (m, 5H), 4.54 (bs, 1H), 3.60 (AB quartet, J = 13 Hz, 2H), 3.35 (m, 1H), 3.11 (dd, J = 14.6 Hz , 1H), 2.93 (m, 2H), 2.41 (dd, J = 10.4 Hz, 1H), 2.31 (d, J = 8 Hz, 1H), 1.44 (s, 9H), 1.23 (m, 1H), 1.07 ( m, 1H), 0.40 (dd, J = 8.4 Hz, 1H).

6. 1-[(N-tert-butoxycarbonyl) aminomethyl)]-azabicyclo [3.1.0] hexane

The title compound of Preparation A.5. (3.27 g, 10.8 mmol) and carbon based 10% palladium (3.44 g) were mixed with ethanol (500 ml), and the resulting suspension was added with ammonium formate (2.04 g, 32.5 mmol). Treated and heated at 60 ° for 7 minutes. The reaction mixture was cooled down, filtered through diatomaceous earth (Celite ™) and then the solid cake was rinsed thoroughly with chloroform. The solvent was removed in vacuo to give an off white residue which was purified by column chromatography (eluant: 89: 10: 1 chloroform: methanol: concentrated ammonium hydroxide) to give the title product as a white solid (1.53 g, 7.2 Mmol, yield 67%). Melting Point 131.5-132.5 ℃

¹ H NMR (CDCl ₃ ): 4.63 (bs, 1H), 3.31 (dd, J = 12, 6 Hz, 1H), 3.24 (m, 1H), 2.88 (m, 4H), 1.40 (s, 9H), 1.23 (m, 1H), 0.54 (m, 1H), 0.42 (m, 1H).

[Manufacture example B]

1. 1-[(N-acetyl) aminomethyl] -3-benzyl-3-azabicyclo [3.1.0] hexane

A mixture of the title compound (1.65 g, 8.16 mmol) and triethylamine (1.7 mL, 12 mmol) of Preparation Example A.4 was treated with acetic anhydride (20 mL) and then stirred at room temperature for 18 hours. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The solvent was removed in vacuo to afford the title product as a viscous yellow oil (1.97 g, 8.06 mmol, 99% yield).

¹ H NMR (CDCl ₃ ): 7.25 (m, 5H), 5.46 (bs, 1H), 3.61 (d, J = 13Hz, 1H), 3.51 (d, J = 13Hz, 1H), 3.48 (m, 1H) , 3.16 (dd, J = 14,5 Hz, 1H), 2.90 (d, J = 9 Hz, 2H), 2.38 (dd, J = 9.3 Hz, 1H), 2.25 (d, J = 9 Hz, 1H), 1.94 ( s, 3H), 1.22 (m, 1H), 1.05 (m, 1H), 0.39 (dd, J = 8.4 Hz, 1H).

2. 1-[(N-acetyl) aminomethyl] -3-azabicyclo [3.1.0] hexane

A solution of the title compound (197.4 mg, 0.80 mmol) of Preparation Example B.1. In ethanol (15 mol) was treated with carbon based palladium (10%, 254.4 mg, 0.24 mmol) and ammonium formate (151.3 mg, 2.4 mmol). It was. The reaction mixture was stirred at room temperature for 30 minutes and then filtered through diatomaceous earth (Celite ™). The colorless filtrate was concentrated in vacuo to afford the title product as a colorless semisolid (149.4 mg, quant.).

¹ H NMR (CDCl ₃ ): 3.42 (s, 2H), 3.25 (m, 4H), 2.00 (s, 3H), 1.6 (m, 1H), 0.84 (m, 1H), 0.71 (m, 1H).

Production Example C

1. 3-benzyl-1- [N- (tert-butoxycarbonyl) ethylaminomethyl] -3-azabicyclo [3.1.0] hexane

The compound of Preparation A.4. (1.1 g, 5.4 mmol) was dissolved in methanol (55 ml), followed by acetic acid (0.31 ml, 5.4 mmol), acetaldehyde (0.30 ml, 5.4 mmol) and sodium borocyanohydride ( 341 mg, 5.4 mmol). The reaction mixture was stirred at rt for 18 h, then diluted with water and methylene chloride and acidified to pH 1 by addition of 6N hydrochloric acid. Potassium carbonate was then added until the pH of the aqueous layer reached 10, the mixture was extracted three times with methylene chloride, and then the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluant: 89: 10: 1 = chloroform: methanol: concentrated ammonium hydroxide) to give a colorless oil (390 mg, 3-benzyl-1-ethylaminomethyl-3-azabicyclo [3.1.0]. ] 2: 1 mixture of hexane and 1-aminomethyl-3-benzyl-3-azabicyclo [3.1.0] hexane). This material was dissolved in dioxane (18 ml) and water (2 ml), then treated with triethylamine (0.7 ml, 5.0 mmol) and di-tert-butyl bicarbonate (1.1 g, 5.0 mmol) and the reaction mixture was cooled to room temperature. Stirred for 18 h. This solution was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted three times with methylene chloride, and then the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting colorless oil was purified on Chromatotron ™ (eluent: 400: 10: 1 = chloroform: methanol: concentrated ammonium hydroxide) to give the title product as a yellow oil (277 mg, 0.84 mmol, 16% yield). ).

¹ H NMR (CDCl ₃ ): 7.30 (m, 5H), 3.65 (bs, 2H), 3.30 (m, 4H), 3.00 (m, 2H), 2.44 (m, 2H), 1.48 (s, 9H), 1.25 (m, 1H), 1.15 (m, 1H), 1.12 (t, J = 7 Hz, 3H), 0.46 (bs, 1H).

2. 1-[(N- (tert-butoxycarbonyl) ethylaminomethyl] -3-azabicyclo [3.1.0] hexane

The title compound (266.2 mg, 0.80 mmol) of Preparation Example C.1. Was dissolved in ethanol (8 ml), treated with ammonium formate (152 mg, 2.4 mmol) and 10% palladium (280 mg) based on carbon, and then at 60 ° C. Heated for 10 minutes. The reaction mixture was filtered through diatomaceous earth (Celite ™), then the filtrate was concentrated in vacuo, the residue was mixed with chloroform, and then filtered once more to remove the solvent to give a colorless oil. This material was purified by silica gel chromatography (eluent; 95: 5: 0.5 = chloroform: methanol: concentrated ammonium hydroxide) to give the title product as a colorless oil (45.6 mg, 0.19 mmol, yield 24%).

¹ H NMR (CDCl ₃ ): 3.43 (bs, 2H), 3.24 (bs, 2H), 2.90 (m, 3H), 2.46 (bs, 2H), 1.42 (s, 9H), 1.22 (bs, 1H), 1.08 (t, J = 7 Hz, 3H), 0.55 (m, 1H), 0.46 (m, 1H).

Preparation Example D

1. 3-benzyl-3-azabicyclo [3.1.0] hexane-1-carboxylic acid

A mixture of 3-benzyl-1-cyano-3-azabicyclo [3.1.0] hexane (2.77 g, 14.0 mmol) and barium hydroxide (4.47 g, 14.2 mmol) in water (100 ml) was heated to reflux for 18 hours. . The reaction was then cooled and adjusted to neutral pH by addition of sulfuric acid. The cloudy white mixture was filtered, washed twice with ethanol and twice with water. The filtrate was concentrated in vacuo and the residue was concentrated to give the title product (2.91 g, 13.4 mmol, 96% yield).

¹ H NMR (D ₂ O): 7.50 (bs, 5H), 4.36 (s, 2H), 3.9 (bs, 1H), 3.6 (m, 1H), 3.5 (bm, 2H), 2.14 (bs, 1H) , 1.53 (bs, 1 H), 1.09 (bs, 1 H).

2. 3-benzyl-1-isopropoxycarbonylamino-3-azabicyclo [3.1.0] hexane

A mixture of the title compound (4.72 g, 21.7 mmol), diphenylphosphoryl azide (4.68 ml, 21.7 mmol) and triethylamine (6 ml, 43 mmol) in Preparation Example D.1. In isopropanol (210 ml) was 80 ° C. Heated at for 18 h. The volatiles were removed in vacuo and the residual oil was dissolved in benzene. The benzene solution was washed with water, aqueous sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. After filtration, the solvent was removed in vacuo to give a thick oil, which was purified by silica gel chromatography (eluant: 289: 10: 1 = chloroform: methanol: concentrated ammonium hydroxide) to give the title product (3.5 g, 12.8 mmol, yield 59%). Melting point 88 캜.

¹ H NMR (CDCl ₃ ): 7.26 (m, 5H), 4.92 (m, 2H), 3.60 (s, 2H), 3.03 (d, J = 8 Hz, 1H), 2.87 (d, J = 9 Hz, 1H) , 2.61 (bs, 1H), 2.51 (d, J = 8 Hz, 1H), 1.52 (bs, 1H), 1.32 (bs, 1H), 1.21 (d, J = 6 Hz, 6H), 0.73 (dd, J = 8,4 Hz, 1H).

3. 1-amino-3-benzyl-3-azabicyclo [3.1.0] hexane

The title compound (1.43 g, 5.21 mmol) of Preparation Example D.2. Was treated with hydrochloric acid (7 ml of 12 M solution) and then heated to 100 ° C. for 18 hours. The reaction was then concentrated in vacuo to give a viscous oil, which was purified by silica gel chromatography (eluent; 189: 10: 10 and then 89:10:10 and chloroform: methanol: concentrated ammonium hydroxide) in 85: 14: 1. . This method gave the title product as an oil (661 mg, 3.51 mmol, yield 67%).

¹ H NMR (CDCl ₃ ): 7.27 (m, 5H), 3.60 (s, 2H), 3.02 (d, J = 8 Hz, 1H), 2.84 (d, J = 9 Hz, 1H), 2.50 (dd, J = 8,4 Hz, 1H), 2.33 (d, J = 8 Hz, 1H), 1.9 (vbs, 2H), 1.18 (m, 1H), 1.09 (m, 1H), 0.63 (dd, J = 8,4 Hz, 1H )

4. 1-acetylamino-3-benzyl-3-azabicyclo [3.1.0] hexane

Acetyl chloride (0.273 ml, 3.85 mmol) in tetrahydrofuran (10 ml) title compound (144.7 mg, 0.77 mmol), dimethylamino pyridine (47 mg, 0.38 mmol) and triethylamine (1.6 ml) in Preparation D.3. , 11.5 mmol) was added dropwise over 5 minutes. The reaction was stirred at rt for 18 h, then the solvent was removed in vacuo and the residue was diluted with methylene chloride. The organic solution was washed with an aqueous sodium bicarbonate solution, followed by saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solution was filtered and concentrated in vacuo to give a dark red oil. Purification by column chromatography (eluent; 189: 10: 10 = chloroform: methanol: concentrated ammonium hydroxide) gave the title product as a yellow oil (89.5 mg, 0.39 mmol, 51% yield).

¹ H NMR (CDCl ₃ ): 7.25 (m, 5H), 5.96 (bs, 1H), 3.60 (m, 2H), 3.07 (d, J = 8Hz, 1H), 2.87 (d, J = 9Hz, 1H) , 2.63 (dd, J = 9,4 Hz, 1H), 2.51 (d, J = 8 Hz, 1H), 1.90 (s, 3H), 1.52 (m, 1H), 1.35 (m, 1H), 0.70 (dd, J = 9,5 Hz, 1H).

5. 1-acetylamino-3-azabicyclo [3.1.0] hexane

The title compound (77.8 mg, 0.34 mmol) of Preparation Example D.4. Was dissolved in ethanol (20 ml), treated with carbon based palladium (10%, 105 mg, 0.09 mmol) and ammonium formate (78 mg, 1.24 mmol) After addition, the reaction mixture was heated to 60 ° C. for 1 hour. The reaction mixture was filtered through diatomaceous earth (Celite ™), the diatomaceous earth was washed well with ethanol and the combined filtrates were concentrated in vacuo to give a yellowish green oil. Purification by silica gel chromatography (eluent; methanol with 1: 1-chloroform: 1% ammonium hydroxide added) afforded the title product as a viscous oil (26.1 mg, 0.186 mmol, yield 55%).

¹ H NMR (CD ₃ OD): 3.10 (m, 2H), 2.87 (d, J = 11Hz, 1H), 2.84 (d, J = 11Hz, 1H), 1.90 (s, 3H), 1.55 (m, 1H ), 0.88 (d, J = 7 Hz, 2H).

Production Example E

1. 5-benzyl-1,3a, 4,5,6,6a-hexahydro-4,6-dioxopyrrolo [3,4-c] pyrazole-3-carboxylic acid, ethyl ester

Ethyl diazoacetate (13 g, 114 mmol) in diethyl ether (100 ml) was added dropwise to a solution of N-benzyl maleimide (10 g, 53 mmol) in diethyl ether (250 ml). The resulting mixture was stirred for 18 hours, then the solvent was removed in vacuo, and the resulting residue was partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title product (16 g, 53 mmol, yield 100%) as a white solid. Melting point 145 ° -146 ° C. (decomposition).

¹ H NMR (CDCl ₃ ): 7.31 (m, 5H), 7.02 (bs, 1H), 4.89 (dd, J = 11, 2 Hz, 1H), 4.65 (s, 2H), 4.55 (d, J = 10 Hz, 1H), 4.36 (q, J = 7 Hz, 2H), 1.37 (t, J = 7 Hz, 3H).

2. [1α, 5α, 6α] -3-benzyl-3-azabicyclo [3.1.0] hexane-2,4-dione-6-carboxylic acid, ethyl ester

The title compound (99 g, 0.33 mol) of Preparation Example E.1 was thermally decomposed in an 185 ° C. oil bath, after 1.5 hours, the reaction was cooled to room temperature, and the product was recrystallized from diethyl ether to give the title product as a white solid. Obtained (31.2 g, 114 mol, yield 35%). Melting point 100-101 ° C.

¹ H NMR (CDCl ₃ ): 7.29 (s, 5H), 4.50 (s, 2H), 4.17 (q, J = 7Hz, 2H), 2.86 (d, J = 3Hz, 2H), 2.28 (t, J = 3 Hz, 1 H), 1.26 (t, J = 7 Hz, 3H).

3. [1α, 5α, 6α] -3-benzyl-6-hydroxymethyl-3-azabicyclo [3.1.0] hexane

A solution of ethyl 3-benzyl-3-azabicyclo [3.1.0] hexane-2,4-dione-6-carboxylate (2.73 g, 10 mmol) was added to lithium aluminum hydride (1.5 g) in tetrahydrofuran (250 ml). , 40 mmol) in suspension. The resulting mixture was heated to reflux for 28 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (2 ml), filtered and the filtrate was concentrated in vacuo to afford the title product as a colorless oil (1.69 g, 8.3 mmol, 83% yield).

¹ H NMR (CDCl ₃ ): 7.27 (m, 5H), 3.58 (s, 2H), 3.43 (d, J = 7 Hz, 2H), 2.96 (d, J = 8 Hz, 2H), 2.35 (bd, J = 9 Hz, 2H), 1.58 (m, 1H), 2.28 (s, 2H).

4. [1α, 5α, 6α] -3-benzyl-3-azabicyclo [3.1.0] hexane-6-carboxaldehyde

Dimethylsulfoxide (0.48 ml, 6.8 mmol) was added to a -65 ° C solution of oxalyl chloride (0.33 ml, 3.8 mmol) in methylene chloride (80 ml). Then a solution of the title compound of Preparation Example E.3. (0.75 g, 3.7 mmol) in methylene chloride (20 ml) was still added to the reaction mixture at -65 ° C. After addition of triethylamine (2.0 ml, 16 mmol), the mixture was allowed to warm to room temperature. The solvent was then removed in vacuo, then the residue was partitioned between water and diethyl ether. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a pale brown oil. Column chromatography (eluent; 20% ethyl acetate in hexanes) gave the title product as a pale green oil (574 mg, 2.85 mmol, 77% yield).

¹ H NMR (CDCl ₃ ): 9.26 (d, J = 5 Hz, 1H), 7.24 (m, 5H), 3.59 (s, 2H), 3.03 (d, J = 9 Hz, 2H), 2.45 (bd, J = 9 Hz, 2H), 2.40 (m, 1H), 2.06 (bs, 2H).

5. [1α, 5α, 6α] -3-benzyl-3-azabicyclo [3.1.0] hexane-6-carboxaldehyde oxime

A solution of the title compound (3.2 g, 16 mmol) of Preparation Example E.4. In ethanol (160 ml) was treated with sodium acetate (4.25 g, 60 mmol) and 3.2 g, 46 mmol of hydroxyamine hydrochloride, followed by 18 Stir for hours. After the solvent was removed in vacuo, the residue was partitioned between methylene chloride and aqueous potassium carbonate solution. The combined organic layers were dried over sodium sulfate and concentrated to give the title product (3.29 g, 15.2 mmol, yield 95%).

¹ H NMR (CDCl ₃ , mixture of geometric isomers around oxime): 7.28 (m, 5H), 7.07 and 6.06 (d, J = 8,9 Hz, 1H), 3.61 and 3.60 (s, 2H), 3.07 and 3.04 (d, J = 9 Hz, 2H), 2.75 and 2.10 (m., 1H), 2.41 (m, 2H), 1.64 (m, 2H).

6. [1α, 5α, 6α] -6-aminomethyl-3-benzyl-3-azabicyclo [3.1.0] hexane

The title compound (3.2 g, 14 mmol) of Preparation Example E.5. Was dissolved in tetrahydrofuran (150 ml) and treated with lithium aluminum hydride (1.85 g, 49 mmol). The resulting suspension was heated to reflux for 12 hours. A saturated solution of water (5 ml) and potassium sodium tartrate (2 ml) was added and the mixture was stirred for 1 hour. Magnesium sulfate was added, then the mixture was filtered and the solvent was removed from the filtrate to give the title product as a yellow oil (2.3 g, 11 mmol, 78% yield).

¹ H NMR (CDCl ₃ ): 7.27 (m, 5H), 3.58 (s, 2H), 2.96 (d, J = 9 Hz, 2H). 2.50 (d, J = 7 Hz, 2H), 2.34 (d, J = 9 Hz, 2H), 1.38 (m, 1H), 1.32 (bs, 2H), 1.19 (bs, 2H).

7. [1α, 5α, 6α] -3-benzyl-6-[(tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hexane

The title compound (150 mg, 0.74 mmol) of Preparation Example E.6. Was dissolved in dioxane (9 ml) and water (1 ml), followed by triethylamine (0.15 ml, 1.1 mmol) and di-tert-butyl bicarbonate (165 mg). , 0.76 mmol). The resulting solution was stirred for 1.5 h and then partitioned between diethyl ether and water. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title product as pale green oil (216 mg, 0.71 mmol, 96% yield).

¹ H NMR (CDCl ₃ ): 7.27 (m, 5H), 4.73 (bs, 1H), 3.57 (s, 2H), 2.97 (m, 4H), 2.34 (bd, J = 9 Hz, 2H), 1.44 (m , 10H), 1.25 (bs, 2H).

8. [1α, 5α, 6α] -6- (tert-butoxycarbonyl) aminomethyl-3-azabicyclo [3.1.0] hexane

A mixture of the title compound of Preparation E.7. (240 mg, 0.79 mmol), carbon based 10% palladium (240 mg) and ammonium formate (240 mg, 3.8 mmol) in ethanol (10 ml) was stirred at room temperature for 0.5 h. The mixture was filtered and concentrated to give a rubbery solid which was mixed with methylene chloride and filtered. The solvent was removed under reduced pressure to give a yellow oil which was crystallized from ethyl ether to give the title product as a white solid (148 mg, 0.70 mmol, yield 89%). Melting point 95-97 ° C.

¹ H NMR (CDCl ₃ ): 8.47 (bs, 1H), 4.80 (bs, 1H), 3.33 (m, 4H), 3.06 (m, 2H), 1.66 (bs, 2H), 1.43 (s, 9H), 1.23 (bs, 1 H).

[Manufacture example F]

1. [1α, 5α, 6α] -6-hydroxymethyl-3-azabicyclo [3.1.0] hexane

[1α, 5α, 6α] -3-benzyl-6-hydroxymethyl-3-azabicyclo [3.1.0] hexane (2.5 g, 12 mmol) was dissolved in methanol (200 mL) and carbon-based palladium hydroxide (20 % Palladium content, 500 mg) and then stirred for 4.5 hours under 1 atmosphere of hydrogen. The reaction mixture was filtered and concentrated in vacuo, then the residue was mixed with acetonitrile and crystallized. Filtration gave the title product as an amorphous white solid (1.16 g, 10.2 mmol, yield 85%). Melting Point 98-100 ℃

¹ H NMR (CDCl ₃ ): 3.46 (d, J = 7 Hz, 2H), 2.98 (d, J = 11 Hz, 2H), 2.85 (bd, J = 12 Hz, 2H), 1.67 (bs, 2H), 1.33 ( m, 2H), 0.89 (m, 1H).

2. [1α, 5α, 6α] -3-benzyloxycarbonyl-6-hydroxymethyl-3-azabicyclo [3.1.0] hexane

The title compound (1.0 g, 8.8 mmol) of Preparation Example F.1. Was dissolved in dioxane (40 ml) and water (40 ml), followed by sodium bicarbonate (3 g, 36 mmol) and benzyl chloroformate (1.3 ml, 9.1 mmol). ). After 30 minutes, the reaction mixture was extracted with ethyl acetate, the combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title product as an oil (2.15 g, 8.7 mmol, 99% yield).

¹ H NMR (CDCl ₃ ): 7.32 (bs, 5H), 5.08 (s, 2H), 3.65 (m, 2H), 3.46 (m, 4H), 1.45 (m, 2H), 0.91 (m, 1H).

3. [1α, 5α, 6α] -3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid

A solution of the title compound (2.1 g, 8.5 mmol) of Preparation F.2. In acetone (50 ml) was treated dropwise with Jones reagent until orange color persisted. Isopropanol was then added to quench the excess oxidant and the resulting mixture was partitioned between water and methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title product as an oil (2.08 g, 8.0 mmol, 94% yield).

¹ H NMR (CDCl ₃ ): 7.32 (bs, 5H), 5.08 (s, 2H), 3.72 (m, 2H), 3.50 (bs, 2H), 2.13 (bs, 2H), 1.47 (t, d = 3Hz 1H).

4. [1α, 5α, 6α] -3-benzyloxycarbonyl-6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane

Diphenylphosphoryl azide (865 μl, 4 mmol), triethylamine (1.1 ml, 8 mmol) and the title compound (1.0 g, 3.83 mmol) of Preparation Example F.3. Were dissolved in t-butanol (45 ml). It was then heated to reflux for 18 hours. The solvent was then removed in vacuo and the residue was partitioned between water and ethyl acetate. The combined organic layers were dried over sodium sulfate and then concentrated to give a residue, which was purified by column chromatography (eluent; 40% ethyl acetate in hexanes). The title product was obtained as an oil (772 mg, 2.3 mmol, yield 60%).

¹ H NMR (CDCl ₃ ): 7.31 (s, 5H), 5.06 (s, 2H), 4.65 (bs, 1H), 3.70 (m, 2H), 3.46 (m, 2H), 2.26 (bs, 1H), 1.67 (bs, 2 H), 1.41 (s, 9 H).

5. [1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane

A solution of the title compound (58 mg, 0.17 mmol) of Preparation Example F.4. Was treated with carbon-based palladium (10 wt%, 60 g) and ammonium formate (60 mg, 1 mmol), followed by 15 minutes at 65 ° C Heated. The reaction mixture was then filtered through Super-cel and the filtrate was concentrated in vacuo to afford the title compound as a solid (28 mg, 0.14 mmol, 82% yield).

¹ H NMR (CDCl ₃ ): 4.65 (bs, 1H), 3.14 (d, J = 12 Hz, 2H), 2.93 (m, 2H), 2.30 (bs, 1H), 1.59 (bs, 2H), 1.44 (s , 9H).

Example G

1. [1α, 5α, 6α] -3-benzyl-4-hydroxy-4-methyl-3-azabicyclo [3.1.0] hexan-2-one-6-carboxylic acid, ethyl ester

Dissolve [1α, 5α, 6α] -3-benzyl-3-azabicyclo [3.1.0] hexane-2.4-dione-6-carboxylic acid, ethyl ester (26 g, 95 mmol) in tetrahydrofuran (800 ml) Then cooled to -78 ° C. Methyllithium (105 ml of 0.98 M solution in ether, 102 mmol) was added dropwise, saturated aqueous ammonium chloride solution was added to the cooled reaction mixture, and then the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, treated with activated charcoal, filtered and concentrated in vacuo to afford the title product as a brown oil (26.86 g, 93 mmol, 98% yield). This was used without purification.

¹ H NMR (CDCl ₃ ): 7.27 (m, 5H), 4.63 (bd, J = 16 Hz, 1H), 4.17 (m, 3H), 2.54 (d, J = 3 Hz, 2H), 1.75 (t, J = 3 Hz, 1 H), 1.63 (s, 1 H), 1.34 (s, 3 H), 1.28 (t, J = 7 Hz, 3 H).

2. [1α, 2β, 5α, 6α] -3-benzyl-6-hydroxymethyl-2-methyl-3-azabicyclo [3.1.0] hexane

The compound of Example G.1. (28 g, 95 mmol) was dissolved in tetrahydrofuran (800 ml), treated with lithium aluminum hydride (18 g, 470 mmol) and heated to reflux for 18 hours. The reaction mixture was then treated with saturated ammonium chloride (30 ml), water (90 ml) and stirred until a white precipitate formed. The solid was filtered off and the filtrate was concentrated in vacuo to give an oil. This was purified by column chromatography (eluent; 20% ethyl acetate in hexanes followed by 40% then ethyl acetate) to give the title product as an oil (10.86 g, 50 mmol, 53% yield).

¹ H NMR (CDCl ₃ ): 7.23 (m, 5H), 3.88 (d, J = 13.5 Hz, 1H), 3.38 (m, 2H), 3.13 (d, J = 13.5 Hz, 1H), 2.90 (d, J = 9 Hz, 1H), 2.69 (m, 1H), 2.30 (dd, J = 9.3 Hz, 1H), 1.76 (bs, 1H), 1.50 (m, 1H), 1.27 (m, 1H), 1.18 (B , 1H). 1.14 (d, J = 6 Hz, 3 H).

3. [1α, 2β, 5α, 6α] -3-benzyl-2-methyl-3-azabicyclo [3.1.0] hexane-6-carboxaldehyde

Dimethylsulfoxide (0.6 ml, 7.8 mmol) was added to a -65 ° C. solution of oxalyl chloride (0.67 ml, 7.7 mmol) in methylene chloride (200 ml). Then a solution of the compound of Example G.2. (1.5 g, 7 mmol) in methylene chloride (500 ml) was added at -65 ° C. Triethylamine (4.3 ml, 30 mmol) was added and the reaction mixture was allowed to warm to room temperature. Hydrochloric acid (3N, 150ml) was added, and then the organic layer was washed with additional amount of hydrochloric acid (3N, 100ml). The aqueous layer was basified with potassium carbonate and then extracted with ether. The combined ether layers were washed with brine, dried over sodium sulfate and then concentrated in vacuo to afford a residue, which was mixed with hexanes, filtered and concentrated to give crude title product as an oil (1.26 g, 5.8 mmol, Yield 83%).

¹ H NMR (CDCl ₃ ): 9.23 (d, J = 5 Hz, 1 H), 7.26 (m, 5 H), 3.91 (d, J = 13.5 Hz, 1 H), 3.15 (d, J = 13.5 Hz, 1 H), 2.95 (d, J = 9 Hz, 1H), 2.85 (m, 1H), 2.42 (dd, J = 9.6, 3.3 Hz, 1H), 2.34 (m, 1H), 2.10 (m, 1H), 2.00 (m, 1H), 1.16 (d, J = 6 Hz, 3H).

4. [1α, 2β, 5α, 6α] -3-benzyl-2-methyl-3-azabicyclo [3.1.0] hexane-6-carboxaldehyde oxime

A solution of the compound of Example G.3. (1.0 g, 4.6 mmol) in ethanol (50 ml) was treated with sodium acetate (1.5 g, 18 mmol) and hydroxyamine hydrochloride (0.915 g, 13 mmol), followed by 1 Stir for hours. After the solvent was removed in vacuo, the residue was partitioned between chloroform and aqueous potassium carbonate solution. The combined organic layers were dried over sodium sulfate and then concentrated. The solid material thus obtained was recrystallized from hexane to give the title product as white needle crystals (729 mg, 3.16 mmol, 69% yield). Melting point 104-107 ° C.

5. [1α, 2β, 5α, 6α] -6-aminomethyl-3-benzyl-2-methyl-3-azabicyclo [3.1.0] hexane

The compound of Example G.4. (4.2G, 18 mmol) was dissolved in tetrahydrofuran (250 ml) and treated with lithium aluminum hydride (4.2 g, 111 mmol). The resulting suspension was heated to reflux for 1 hour. Saturated aqueous sodium chloride solution (24 ml) and water (5 ml) were added and the resulting precipitate was filtered and the filtrate was concentrated to give crude product as an oil (3.68 g, 17 mmol, 94% yield).

¹ H NMR (CDCl ₃ ): 7.23 (m, 5H), 3.87 (dd, J = 13.5 Hz, 1H), 3.11 (d, J = 13.5 Hz, 1H), 2.88 (d, J = 9, 0 Hz, 1H ), 2.66 (m, 1H), 2.45 (m, 2H), 2.28 (dd, J = 9, 4 Hz, 1H), 1.54 (bs, 2H), 1.30 (m, 1H), 1.18 (m, 1H), 1.12 (d, J = 5.9 Hz, 3H), 1.09 (m, 1H).

6. [1α, 2β, 5α, 6α] -6- (tert-butoxycarbonyl) aminomethyl-2-methyl-3-azabicyclo [3.1.0] hexane

The compound of Example G.5. (3.4 g, 15.7 mmol) was dissolved in dioxane (50 ml) and water (6 ml) followed by treatment with di-tert-butyl bicarbonate (3.4 g, 15.7 mmol). The reaction solution was stirred for 1 hour and then concentrated in vacuo. The resulting material was purified by column chromatography (eluent; 20% ethyl acetate in hexanes) to give the title product as a white solid (4.8 g, 15.2 mmol, 97% yield).

7. [1α, 2β, 5α, 6α] -6- (tert) -butoxycarbonyl) aminomethyl-2-methyl-3-azabicyclo [3.1.0] hexane

A mixture of the compound of Example G.6. (3.4 g, 11 mmol) and 10% palladium hydroxide (3.5 g) in methanol (350 ml) was treated with hydrogen at atmospheric pressure for 18 hours. After filtration, the solvent was removed in vacuo to afford the crude product, which was purified by column chromatography (eluent; 89: 10: 10 = chloroform: methanol: concentrated ammonium hydroxide). Treatment with ether gave the title product as a white solid (1.86 g, 8.2 mmol, yield 75%). Melting point 89.5 ° -91.5 ° C.

¹ H NMR (CDCl ₃ ): 4.82 (bs, 1H), 3.16 (m, 1H), 2.89 (m, 2H), 2.81 (m, 2H), 1.33 (s, 10H), 1.16 (m, 2H), 1.00 (d, J = 6.3 Hz, 3H), 0.72 (m, 1H).

Example H

1. [1α, 2β, 5α, 6α] -6-hydroxymethyl-2-methyl-3-azabicyclo [3.1.0] hexane aldehyde

[1α, 2β, 5α, 6α] -3-benzyl-6-hydroxymethyl-2-methyl-3-azabicyclo [3.1.0] hexane (4.2 g, 19.3 mmol) was dissolved in methanol (150 mmol) And treated with carbon-based palladium hydroxide (10% palladium content, 3.0 g), followed by stirring for 18 hours under 1 atmosphere of hydrogen. The reaction mixture was filtered and then concentrated in vacuo to afford the title product as a white solid (2.45, 19.3 mmol, yield 100%). Melting point 85 ° -87 ° C.

¹ H NMR (CDCl ₃ ): 3.39 (dd, J = 7, 10 Hz, 1H), 3.28 (dd, J = 7, 9 Hz, 1H), 3.19 (m, 1H), 2.84 (m, 4H), 1.24 ( m, 2H), 1.05 (d, J = 6 Hz, 3H), 0.82 (m, 1H).

2. [1α, 2β, 5α, 6α] -3-benzyloxycarbonyl-6-hydroxymethyl-2-methyl-3-azabicyclo [3.1.0] hexane

Example H.1. Compound (2.3 g, 18 mmol) was dissolved in dioxane (50 ml) and water (50 ml), then treated with saturated aqueous bicarbonate solution (50 ml) and benzyl chloroformate (2.8 ml, 19 mmol). It was. After 18 hours, the reaction mixture was partitioned between ether and water, and the combined organic layers were dried over sodium sulfate, filtered and then concentrated in vacuo. The residue is purified by column chromatography (eluent; 50% ethyl acetate in hexanes) to give the title product as an oil (3.68 g, 14 mmol, 78% yield).

¹ H NMR (CDCl ₃ ): 7.30 (m, 5H), 5.18 (AB quartet, J = 12.5 Hz, 2H), 3.98 (m, 1H), 3.54 (d, J = 2 Hz, 2H), 3.43 (m , 2H), 2.31 (s, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.32 (d, J = 6 Hz, 3H), 1.02 (m, 1H).

3. [1α, 2β, 5α, 6α] -3-benzyloxycarbonyl-2-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid

A solution of the compound of Example H.2 (3.2 g, 12 mmol) in acetone (100 ml) was added dropwise with Jones reagent until orange color persisted. The excess oxidant was then quenched by addition of isopropanol and the resulting mixture was partitioned between water and methylene chloride. The glass layer was dried over sodium sulfate, filtered and concentrated to give a residue, which was mixed with ether, dried once more over sodium sulfate, filtered and concentrated in vacuo to give the title product as a rubber (3.06 g, 11.1 mmol, yield 63%).

¹ H NMR (CDCl ₃ ): 10.2 (vbs, 1H), 7.33 (m, 5H), 5.09 (m, 2H), 4.08 (m, 1H), 3.64 (bs, 2H), 2.27 (m, 1H), 2.09 (m, 1 H), 1.59 (t, J = 3 Hz, 1 H), 1.38 (bs, 3H).

4. [1α, 2β, 5α, 6α] -3-benzyloxycarbonyl-6-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hexane

Diphenylphosphoryl azide (2.3 ml, 10.6 mmol), triethylamine (2.85 ml, 20 mmol) and the compound of Example H.3 (2.85 g, 10 mmol) were dissolved in t-butanol (120 ml). Then heated to reflux for 18 hours. The solvent was then removed in vacuo and the residue was purified by column chromatography (eluant: 20% ethyl acetate in hexanes). The title product was obtained as a solid (11.7 g, 4.9 mmol, yield 49%). Melting point 118 ° -120 ℃

5. [1α, 2β, 5α, 6α] -6-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0.] Hexane

A solution of the compound of Example H.4 (1.5 g, 4.3 mmol) and the like in methanol (150 ml) was treated with carbon-based palladium hydroxide (10% palladium content, 1.5 g), followed by stirring for 2.5 hours under 1 atmosphere of hydrogen. . The catalyst was filtered off and the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (eluent; 89: 10: 10 = chloroform: methanol: concentrated ammonium hydroxide) to give the title product as a rubber ( 771 mg, 3.6 mmol, yield 84%).

¹ H NMR (CDCl ₃ ): 9.15 (vbs, 1H), 4.72 (s, 1H), 3.94 (m, 1H), 3.56 (bd, J = 11 Hz, 1H), 3.35 (m, 1H), 2.88 (s , 1H), 1.86 (m, 1H), 1.81 (m, 1H), 1.58 (d, J = 6.2 Hz, 3H), 1.40 (s, 9H).

Example I

1.N-benzyl-N- (1-cyanoprop-2-yl) -3-amino-1,2-propanediol

A solution of glycidol (70 ml, 1.05 mol) and 3- (benzylimino) butyronitrile (111 g, 0.64 mol) in ethanol (800 ml) was heated to reflux for 18 hours. An additional amount of glycidol (50 ml, 0.75 mol) was added and the mixture was heated to reflux for 24 hours. The solvent was removed in vacuo to give a residue, which was partitioned between water and ethyl acetate. The organic layer was washed with water, saturated sodium chloride solution and then dried over sodium sulfate. After filtration, concentration in vacuo gave an oil which was purified by column chromatography (eluent; 5% methanol in chloroform) to give the title product as an oil.

¹ H NMR (CDCl ₃ ): 7.31 (m, 5H), 3.77 (d, J = 13.4 Hz, 1H), 3.67 (m, 3H), 3.49 (d, J = 13.5 Hz, 1H), 3.43 (m, 1H), 3.18 (m, 1H), 2.55 (m, 4H, 2.30 (m, 1H), 1.16 and 1.08 (d, J = 6.5 Hz, 3H).

2. [1α, 2β, 5α] -3-benzyl-1-cyano-2-methyl-3-azabicyclo [3.1.0] hexane [1α, 2α, 5α] -3-benzyl-1-cyano- 2-methyl-3-azabicyclo [3.1.0] hexane

A solution of the compound of Example I.1 (7.5 g, 30 mmol) and triethylamine (10.6 ml, 76 mmol) in chloroform (300 ml) was treated with methanesulfonyl chloride (5.2 ml, 67 mmol). After 1 hour, the reaction mixture was partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to afford a crude bis-mesylate derivative. It was dissolved in tetrahydrofuran (50 ml) and then added dropwise to a solution of sodium hexamethyldisalazide (62 ml of 1N solution in tetrahydrofuran, 62 mmol) in tetrahydrofuran (300 ml). After 1 hour, the reaction mixture was poured into saturated ammonium chloride solution (500 ml) and ether (300 ml). The aqueous layer was extracted with additional ether, and then the combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting brown oil was purified by column chromatography (eluent; 20% ethyl acetate in hexane) to [1α, 2α, 5α] -3-benzyl-1-cyano-2-methyl-3-azabicyclo [3.1. 0] hexane (0.97 g, 4.6 mmol, yield 15%) and [1α, 2β, 5α] -3-benzyl-1-cyano-2-methyl-3-azabicyclo [3.1.0] hexane (0.84 g, 4.00 mmol, yield 13%) was obtained.

¹ H NMR (CDCl ₃ ) for [1α, 2β, 5α] isomer: 7.24 (m, 5H), 3.88 (d, J = 13.6 Hz, 1H), 3.19 (d, J = 13.5 Hz, 1H), 2.88 (qmJ = 6 Hz, 1H), 2.85 (d, J = 9.6 Hz, 1H), 2.42 (dd, J = 9.2, 3.7 Hz, 1H), 1.95 (m, 1H), 1.48 (apparent t, J = 4.9, 4.6 Hz, 1H), 1.25 (d, J = 5.9 Hz, 3H), 0.97 (dd, J = 8.2, 5.1 Hz, 1H).

¹ H NMR (CDCl ₃ ) for [1α, 2β, 5α] isomer: 7.24 (m, 5H), 3.69 (d, J = 13.5 Hz, 1H), 3.57 (d, J = 13.5 Hz, 1H), 3.31 (d, J = 6.6 Hz, 1H), 2.73 (m, 2H), 2.03 (m, 1H), 1.60 (apparent t, J = 5.0, 4.5 Hz, 1H), 1.14 (d, J = 6.7 Hz, 3H ), 1.13 (m, 1 H).

3. [1α, 2β, 5α] -1-aminomethyl-3-benzyl-2-methyl-3-azabicyclo [3.1.0] hexane

Lithium aluminum hydride (4.3 ml of 1M solution in tetrahydrofuran, 4.3 mmol) was dissolved in [1α, 2β, 5α] -3-benzyl-1-cyano-2-methyl-3-azabicyclo [in tetrahydrofuran (10 ml). 3.1.0] was added to a solution of hexane (224 mg, 1.05 mmol). After 18 h at rt, the reaction mixture was treated with water (0.16 ml), sodium hydroxide (0.16 ml 15% aqueous solution) and water (0.48 ml) in that order. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title product as a pale yellow oil (213.3 mg, 0.99 mmol, 94% yield).

¹ H NMR (CDCl ₃ ): 7.24 (m, 5H), 3.91 (d, J = 13.5 Hz, 1H), 3.16 (d, J = 13.6 Hz, 1H), 2.95 (d, J = 13.5 Hz, 1H) , 2.83 (d, J = 8.9 Hz, 1H), 2.68 (q, J = 5.9 Hz, 1H), 2.61 (d, J = 13.5 Hz, 1H), 2.28 (dd, J = 8.9, 3.6 Hz, 1H) , 1.19 (bs, 2H), 1.13 (m, 1H), 1.11 (d, J = 5.6 Hz, 3H), 0.88 (apparent t, J = 4.4, 3.5 Hz, 1H), 0.20 (dd, J = 8.0, 4.3 Hz, 1H).

4. [1α, 2β, 5α] -3-benzyl-1-[(N-acetyl) aminomethyl] -2-methyl-3-azabicyclo [3.1.0] hexane

A solution of the compound of Example I.3 (213 mg, 0.98 mmol) and triethylamine (0.2 ml, 1.47 mmol) in acetic anhydride (5 ml) was stirred at room temperature for 18 hours. The reaction solution was then diluted with chloroform and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil which was purified by column chromatography (eluent; 189: 10: 10 = chloroform: methanol: concentrated ammonium hydroxide) as the title product as an oil. Was obtained (168 mg, 0.65 mmol, yield 66%).

¹ H NMR (CDCl ₃ ): 7.26 (m, 5H), 5.46 (bs, 1H), 3.93 (d, J = 13 Hz, 1H), 3.54 (dd, J = 13,6 Hz, 1H), 3.23 (m, 2H), 2.86 (d, J = 9 Hz, 1H), 2.63 (m, 1H), 2.31 (m, 1H), 1.99 (s, 3H), 1.19 (m, 1H), 1.14 (d, J = 6 Hz, 3H), 0.98 (bs, 1H), 0.28 (dd, J = 8, 4 Hz, 1H).

5. [1α, 2β, 5α] -1-[(N-acetyl) aminomethyl] -2-methyl-3-azabicyclo [3.1.0] hexane

The compound of Example I.4. (164 mg, 0.63 mmol) and carbon based 10% palladium (200 mg) were mixed with ethanol (15 ml). The resulting suspension was treated with ammonium formate (119 mg, 1.89 mmol) and then heated to 60 ° C. for 40 minutes. The reaction mixture was filtered through diatomaceous earth (Celite ™) and then the solid cake was rinsed thoroughly with ethanol. The solvent was removed in vacuo to give the title product as a viscous oil (101.4 mg, 0.62 mmol, yield 96%).

¹ H NMR (CDCl ₃ ): 5.46 (bs, 1H), 3.50 (dd, J = 14.3, 5.7 Hz, 1H), 3.30 (dd, J = 14.3, 5.8 Hz, 1H), 3.15 (q, J = 6.2 Hz, 1H), 2.93 (dd, J = 11.3, 3.1 Hz, 1H), 2.81 (d, J = 11.2 Hz, 1H), 1.96 (s, 3H), 1.28 (m, 1H), 1.08 (d, J = 6.4 Hz, 3H), 0.42 (m, 2H).

Example J

1. [1α, 2β, 5α] -3-benzyl-2-methyl-3-azabicyclo [3.1.0] hexane-1-carboxylic acid hydrochloride

[1α, 2β, 5α] -3-benzyl-1-cyano-2-methyl-3-azabicyclo [3.1.0] hexane (2.25 g, 10.6 mmol) in water (100 mL) and barium hydroxide octahydrate (5.0 g, 15.8 mmol) was heated to reflux for 5 days. The reaction was then acidified by addition of 6N hydrochloric acid and then water was removed in vacuo. Ethanol was added to the residue, the inorganic salts were filtered off and the filtrate was concentrated in vacuo. Treatment with chloroform gave a white solid which was recrystallized from chloroform to give the title product (2.5 g, 9.3 mmol, yield 88%). Melting point 228 ° -229 ° C.

2. [1α, 2β, 5α] -3-benzyl-1-[(N-tert-butoxycarbonyl) amino] -2-methyl-3-azabicyclo [3.1.0] hexane

A solution of the compound of Example J.1. (2.5 g, 9.3 mmol) in acetone (15 ml) and water (15 ml) was treated with ethyl chloroformate (0.92 ml, 9.6 mmol) and stirred for 30 minutes. Then azide sodium (625 mg, 9.6 mmol) was added. After 1 hour, the reaction mixture was partitioned between water and ether. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo and the resulting oil was dissolved in toluene (10 ml) and then heated to 100 ° C. for 1 hour. After tert-butanol (40 ml) was added, the reaction solution was heated to reflux for 18 hours. The solvent was removed in vacuo to give a residue, which was purified by column chromatography (eluent; 20% ethyl acetate in hexanes) to give the title product (1.46 g, 4.83 mmol, yield 52%) as a solid. Melting point 91 ° -92 ° C.

3. [1α, 2β, 5α] -1-[(N-tert-butoxycarbonyl) amino-2-methyl-3-azabicyclo [3.1.0] hexane

The compound of Example J.2 (380 mg, 1.25 mmol) was dissolved in methanol (50 ml), treated with carbon based sodium hydroxide (10% palladium content, 350 mg) and then hydrogenated for 2 hours (30 psi hydrogen). ) The reaction mixture was filtered and concentrated in vacuo to afford a residue, which was purified by column chromatography (eluant: 89:10:10 = chloroform: methanol: concentrated ammonium hydroxide) to give the title product (136 mg) as a white solid. , 0.64 mmol, yield 51%) was obtained. Melting point 132 ° -135 ° C.

¹ H NMR (CDCl ₃ ): 5.35 and 5.19 (bs, 1H), 3.17 (m, 1H), 3.05 (m, 1H), 2.65 (d, J = 11.6 Hz, 1H), 1.43 (m, 1H), 1.30 (s, 9H), 0.97 (d, J = 6.3 Hz, 3H), 0.63 (m, 2H).

Example K

1. [1α, 2α, 5α] -3-benzyl-2-methyl-3-azabicyclo [3.1.0] hexane-1-carboxylic acid hydrochloride

[1α, 2α, 5α] -3-benzyl-1-cyano-2-methyl-3-azabicyclo [3.1.0] hexane (1.4 g, 6.6 mmol) was mixed with hydrochloric acid (12N, 50 ml), Heated to reflux for 18 hours. The solvent was removed in vacuo to give a residue, which was purified by column chromatography (eluent; 89: 10: 10: 1 chloroform: methanol: concentrated ammonium hydroxide) to give the title compound as a rubbery solid (1.4 g, 4.8). Mmol, yield 73%). The sample was prepared by recrystallization from acetone. Melting point 157 ° -158 ° C.

¹ H NMR (CDCl ₃ ): 7.28 (m, 5H), 3.75 (d, J = 13.6 Hz, 1H), 3.59 (d, J = 13.6 Hz, 1H), 3.39 (q, J = 6.3 Hz, 1H) , 2.76 (d, J = 8.8 Hz, 1H), 2.67 (dd, J = 8.8, 3.2 Hz, 1H), 2.08 (m, 1H), 1.73 (m, 1H), 1.18 (m, 1H), 1.15 ( d, J = 6.3 Hz, 3H).

2. [1α, 2α, 6α] -3-benzyl-1-[(N-tert-butoxycarbonyl) amino] -2-methyl-3-azabicyclo [3.1.0] hexane

The title compound was synthesized from the compound of Step 1 according to the method of Example H.4. The product was obtained in 43% yield. The analytical sample was prepared by recrystallization from hexane to obtain a solid. Melting point 141 ° -142 ° C.

¹ H NMR (CDCl ₃ ): 7.26 (m, 5H), 5.03 (bs, 1H), 3.64 (AB quartet, J = 13.7 Hz, 2H), 3.33 (bm, 1H), 2.77 (bm, 1H), 2.60 (d, J = 8.8 Hz, 1H), 1.48 (m, 2H), 1.42 (s, 9H), 0.97 (d, J = 6.5 Hz, 3H), 0.85 (m, 1H).

3. [1α, 2α, 6α] -1-[(N-tert-butoxycarbonyl) amino] -2-methyl-3-azabicyclo [3.1.0] hexane

The title compound was prepared from the compound of Step 2 according to the method of Example H.5 except that the hydrolysis was performed at 30 psi. The product was obtained in a yield of 85%. The analytical sample was prepared by recrystallization from secondary chromatography (eluant: 89: 10: 1 = chloroform: methanol: concentrated ammonium hydroxide), and then ether to obtain a white solid. Melting point 93 ° -95 ° C.

¹ H NMR (CDCl ₃ ): 5.01 (bs, 1H), 3.41 (m, 1H), 3.15 (dd, J = 11.5, 3.2 Hz, 1H), 2.69 (d, J = 11.5 Hz, 1H), 1.54 ( m, 1H), 1.43 (s, 9H), 1.08 (d, J = 6.7 Hz, 3H), 0.90 (m, 2H).

Example L

1. [1α, 5α, 6α] -3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid, ethyl ester and [1α, 5α, 6β] -3-benzyloxycarb Bonyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid, ethyl ester

A solution of ethyl diazoacetate (5.8 ml, 55 mmol) in methylene chloride (32 ml) was added with 1-benzyloxycarbonyl-3-pyrrolin (9.25 g, 50.0 mmol) in methylene chloride (140 ml) and rhodium acetate (1.0 g). , 2.3 mmol) was added slowly (using a syringe pump, over 70 hours). At the end of the addition the reaction mixture was filtered through Celite and then concentrated in vacuo. The residue was purified by column chromatography (eluent; 10% ethyl acetate in hexanes) to give the recovered starting material (3.2 g, 17.3 mmol) and the title product.

[1α, 5α, 6α] -3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid, ethyl ester (2.61 g, 9.02 mmol, yield 28 based on recovered starting material %).

¹ H NMR (CDCl ₃ ): 7.32 (m, 5H), 5.08 (s, 2H), 4.10 (q, J = 7.4 Hz, 2H), 3.71 (dd, J = 14, 11.4 Hz, 2H), 3.49 ( m, 2H), 2.07 (m, 2H), 1.46 (m, 1H), 1.23 (t, J = 7.4 Hz, 3H).

[1α, 5α, 6α] -3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid, ethyl ester (5.4 g, 18.7 mmol, yield 57 based on recovered starting material %).

¹ H NMR (CDCl ₃ ): 7.30 (m, 5H), 5.06 (s, 2H), 3.97 (q, J = 7 Hz, 2H), 3.80 (d, J = 11.2 Hz, 2H), 3.49 (m, 2H ), 1.87 (m, 2H), 1.75 (m, 1H), 1.12 (t, J = 7 Hz, 3H).

2. [1α, 5α, 6α] -3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid

Hydroxide a solution of [1α, 5α, 6β] -3-benzyloxycarbonyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid, ethyl ester (2.0 g, 6.9 mmol) in methanol (200 ml) Treated with aqueous sodium solution (15% by weight, 200ml). After 2 h at rt, the reaction mixture was concentrated in vacuo, extracted with methylene chloride and acidified to pH 2 by addition of 6N hydrochloric acid. The organic extract was decanted and the aqueous layer extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title product as a solid (1.36 g, 5.2 mmol, 75% yield). Melting point 101 ° -102 ° C.

¹ H NMR (CDCl ₃ ): 7.33 (m, 5H), 5.10 (d, J = 5.3 Hz, 2H), 3.87 (d, J = 11.4 Hz, 2H), 3.61 (bd, J = 11.1 Hz, 2H) , 2.03 (m, 2 H), 1.83 (m, 1 H.).

3. [1α, 5α, 6β] -3-benzyloxycarbonyl-6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane

The title product was prepared from the compound of step 2 by the method described in Example H.4, except the reaction was run for 48 hours, and column chromatography was performed using 40% ethyl acetate in hexanes. The title product was obtained in 60% yield and the analytical sample was recrystallized from hexane-ether to give a solid. Melting point 99 ° -103 ° C.

¹ H NMR (CDCl ₃ ): 7.31 (m, 5H), 5.09 (s, 2H), 4.40 (bs, 1H), 3.63 (m, 2H), 3.47 (m, 2H), 2.80 (m, 1H), 1.77 (m, 2 H), 1.39 (s, 9 H).

4. [1α, 5α, 6β] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.] Hexanedehydrate

The solution of the compound of step 3 (1.25 g, 3.75 mmol) in ethanol (50 mL) was treated with carbon based palladium (200 mg) and then placed under Parr hydrogenation conditions (30 psi hydrogen) for 2.5 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to afford a residue, which was chromatographed (eluent; 89: 10: 10 = chloroform: methanol: concentrated ammonium hydroxide) to give the title product (682 mg, 3.44 mmol). , Yield 91%). The analytical sample was recrystallized from hexane to give a white solid. Melting point 85 ° -86 ° C.

¹ H NMR (CDCl ₃ -MeOH-d ₄ ): 3.55 (bd, J = 11.7 Hz, 2H), 3.32 (d, J = 12.3 Hz, 2H), 2.68 (t, J = 6.8 Hz, 1H), 1.99 (m, 2 H), 1.42 (s, 9 H).

Example M

1. [1α, 5α, 6α] -3-benzyloxycarbonyl-6- (N-methyl) tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane

[1α, 5α, 6α] -3-benzyloxycarbonyl-6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (1.25 g, 3.75 mmol) in tetrahydrofuran (10 ml) A solution of methyl iodide (1.9 ml, 30.5 mmol) was treated in portions with sodium hydride (60% in oil, 500 mg, 75 mmol). The resulting mixture was stirred at room temperature for 2.5 hours and then poured into saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and then the combined organic layers were dried over sodium sulfate, filtered and then concentrated in vacuo. The resulting material was purified by column chromatography (eluent; 20% ethyl acetate in hexanes) to give the title product as an oil (1.12 g, 3.23 mmol, yield 86%).

¹ H NMR (CDCl ₃ ): 7.32 (m, 5H), 5.08 (s, 2H), 3.68 (m, 2H), 3.46 (m, 2H), 2.80 (s, 3H), 2.20 (bs, 1H), 1.76 (bs, 2 H), 1.43 (s, 9 H).

2. [1α, 5α, 6α] -6- (N-methyl) tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane

The solution of the compound of step 1 (1.3 g, 3.75 mmol) in methanol (50 ml) was treated with carbon based palladium hydroxide (500 mg) and then placed under Parr hydrogenation reaction conditions (30 psi hydrogen, room temperature). After 2 hours, the catalyst was filtered off and the filtrate was concentrated in vacuo. The title product was obtained as an off-white solid (773 mg, 3.64 mmol, yield 97%). Analytical samples were prepared by treatment with ether to give a solid. Melting point 159 ° -162 ° C.

¹ H NMR (CDCl ₃ ): 6.50 (vbs, 1H), 3.45 (d, J = 11.9 Hz, 2H), 3.35 (d, J = 11.5 Hz, 2H), 2.77 (s, 3H), 2.62 (bs, 1H), 1.92 (bs, 2H), 1.42 (s, 9H).

Example N

1.1-benzyloxycarbonyl-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid, methyl ester

A solution of 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid and hydrochloride (1.8 g, 10 mmol) in methylene chloride (60 ml) was cooled to 0 deg. Benzyl chloroformate (2.74 ml, 19.2 mmol) was added, followed by triethylamine (7.2 ml, 51.2 mmol) and stirred at room temperature for 12 hours. The reaction mixture was washed with brine and then dried over magnesium sulfate. Evaporation in vacuo gave a yellow oil. This was chromatographed on silica gel (eluent; 20%, then 30% ethyl acetate / hexanes) to give the product as a pale yellow oil (2.14 g, 7.7 mmol, yield 77%).

¹ H NMR (CDCl ₃ ): 7.35-7.33 (m, 5H), 7.05 (m, 1H), 5.14 (s, 2H), 4.18 (d, J = 2.3 Hz, 2H), 3.73 (s, 3H), 3.53 (t, J = 5.5 Hz, 2H), 2.30 (m, 2H).

2. 1-benzyloxycarbonyl-3-hydroxymethyl-1,2,5,6-tetrahydropyridine

DIBAL-H was added to a solution of the compound of step 1 (2.0 g, 7.33 mmol) in tetrahydrofuran (30 ml) at −20 ° C. The mixture was allowed to warm up to 0 ° C. and then stirred at this temperature for 5 hours. At 0 ° C. methanol (5 ml) was added followed by a saturated solution of Rossel salt (10 ml) to give a white slurry. After stirring for 2 h more, it was filtered and the filtrate was extracted with ether, then the organic layer was washed with brine and dried over magnesium sulfate. After evaporation the title compound was obtained as a pale yellow oil (1.14 g, 4.6 mmol, 63% yield).

¹ H NMR (CDCl ₃ ): 7.34 (m, 5H), 5.80 (m, 1H), 5.13 (s, 2H), 4.03 (bs, 2H), 3.98 (d, J = 2.0 Hz, 2H), 3.53 ( t, J = 6.0 Hz, 2H), 2.14 (m, 2H).

3. 3-benzyloxycarbonyl-1-hydroxymethyl-3-azabicyclo [4.1.0] heptane

The flask containing samarium metal (6.54 g, 43.5 mmol) was salt dried and then filled with tetrahydrofuran (50 ml). Tetrahydrofuran solution (25 ml) of mercury chloride (1.12 g, 4.14 mmol) was added and then the mixture was stirred for 10 minutes. After the product of step 2 (2.56 g, 10.4 mmol) was added, the reaction mixture was cooled to -78 ° C and chloroiodomethane (3.01 ml, 41.4 mmol) was added dropwise. The mixture was then stirred overnight at room temperature. The reaction mixture was quenched with contained K ₂ CO ₃ and then extracted with ether, the ether layer was washed with brine, dried over MgSO ₄ and concentrated to give a yellow oil. This crude material was chromatographed on silica gel (eluant: 50% ethyl acetate / hexanes) to yield the title compound as a colorless liquid (1.62 g, 6.2 mmol, 60% yield).

¹ H NMR (CDCl ₃ ): 7.37-7.27 (m, 5H), 5.10 (s, 2H), 3.83 (m, 1H), 3.62 (m, 1H), 3.42 (m, 3H), 3.08 (m, 1H ), 1.95 (m, 1H), 1.67 (m, 1H), 0.96 (m, 1H), 0.61 (m, 1H), 0.37 (t, J = 5.1 Hz, 1H).

4. 3-benzyloxycarbonyl-3-azabicyclo [4.1.0] heptane-1-carboxylic acid

To a solution of the compound of step 3 (580 mg, 2.22 mmol) in acetone (10 ml) was added Jones reagent (2.8 ml) at 0 ° C. The mixture was stirred at this temperature for 1 hour. After addition of methanol (5 ml), the reaction mixture was allowed to warm to room temperature and diluted with water. The product was extracted with methylene chloride and the combined organic layers were washed with brine and then dried over magnesium sulfate. The solvent was removed in vacuo to afford the title compound as a white solid (570 mg, 2.1 mmol, 93% yield).

¹ H NMR (CDCl ₃ ): 7.32 (m, 5H), 5.11 (s, 2H), 3.97 (m, 2H), 3.45 (m, 1H), 3.06 (m, 1H), 2.03 (m, 1H), 1.78 (m, 2H), 1.47 (m, 1H), 0.81 (t, J = 5.3 Hz, 1H).

5. 3-benzyloxycarbonyl-1- (tert-butoxycarbonyl) amino-3-azabicyclo [4.1.0] hexane

Triethylamine (0.303 ml, 2.16 mmol) was added to a solution of the compound of step 4 (540 mg, 1.96 mmol) in acetone (8 ml) and the resulting solution was cooled to 0 ° C. in an ice bath. Ethyl chloroformate (0.224 ml, 2.35 mmol) was added slowly, then the mixture was stirred for 30 minutes. A solution of sodium azide (1.27 g, 19.6 mmol) in water (4 ml) was added and stirring was continued at 0 ° C. for 2 h. The reaction mixture was diluted with water and extracted with ether. The organic layer was then washed with brine, dried over magnesium sulfate and concentrated on a rotary evaporator at 25 ° -30 ° C. with a water bath to give azide acyl as a yellow oil.

A solution of tosylated pyridium (1.5 mg, catalyst amount) in t-butyl alcohol (4.5 ml) and toluene (20 ml) was heated to 105 ° C. A solution of azide acyl in toluene (5 ml) was added dropwise, and the resulting solution was stirred overnight at reflux.

After cooling to room temperature, toluene was removed on a rotary evaporator to yield a light brown oil. The crude product was chromatographed on silica gel (eluent; 25%, then 40% ethyl acetate / hexanes) to give the title compound as a colorless liquid (478 mg, 1.38 mmol, 71% yield).

¹ H NMR (CDCl ₃ ): 7.31-7.27 (m, 5H), 5.09 (s, 2H), 4.90 (bs, 1H), 4.12 (bd, J = 2.0 Hz, 1H), 3.55 (m, 1H), 3.47 (m, 1H), 3.05 (m, 1H), 2.09 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.27 (m, 1H), 0.80 (m, 1H), 0.51 (t, J = 5.9 Hz, 1 H).

6. 1- (tert-butoxycarbonyl) amino-3-azabicyclo [4.1.0] hexane

To a solution of the compound of step 5 (1.24 g, 3.58 mmol) in ethanol (20 mL) was added ammonium formate (678 mg, 10.76 mmol) followed by palladium (10% palladium content, 113.8 mg, 1.1 mmol) based on activated carbon. The mixture was stirred at rt for 23 h. The solid material was filtered off and the filtrate was concentrated on a rotary evaporator to give the title compound as a pale yellow solid (1.78 g, recovered at least 100% by weight).

¹ H NMR (CDCl ₃ ): 5.90 (bs, 1H), 5.26 (m, 1H), 3.29 (m, 1H), 3.22 (m, 1H), 2.84 (m, 1H), 2.65 (m, 1H), 2.16 (m, 1H), 1.68 (m, 1H), 1.40 (s, 9H), 1.25 (m, 1H), 0.95 (m, 1H), 0.78 (m, 1H).

Example O

1. [1α, 5β, 6α] -3-benzyloxycarbonyl-5-hydroxy-3-azabicyclo [4.1.0] hexane

The flask containing samarium metal (2.7 g, 18.0 mmol) was salt dried and then filled with tetrahydrofuran (40 ml). Tetrahydrofuran solution (30 ml) of mercury chloride (467 mg, 1.72 mmol) was added and then the mixture was stirred for 10 minutes. After addition of 1-benzyloxycarbonyl-5-hydroxy-1,2,5,6-tetrahydropyridine, the flask was cooled to -78 ° C and chloroiodomethane (1.25 ml, 17.2 mmol) was added dropwise. It was. The mixture was stirred overnight at room temperature, quenched with saturated aqueous K ₂ CO ₃ solution and then extracted with ether. The ether layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo to give a yellow oil. This crude material was chromatographed on neutral alumina-activity I (eluent; 50% ethyl acetate / hexanes) to afford the title compound as a colorless liquid (750 mg, 3.0 mmol, 81% yield).

¹ H NMR (CDCl ₃ ): 7.34 (m, 5H), 5.10 (s, 2H), 4.21 (bs, 1H), 3.68 (d, J = 13.2 Hz, 1H), 3.59 (dd, J = 13.4, 5.2 Hz, 1H), 3.36 (dd, J = 13.9, 4.9 Hz, 1H), 3.16 (dd, J = 13.9, 5.6 Hz, 1H), 1.44 (m, 1H), 1.32 (bm, 1H), 0.65 (m , 1H), 0.49 (q, J = 5.2 Hz, 1H).

2. [1α, 5β, 6α] -3-benzyl-5-hydroxy-3-azabicyclo [4.1.0] heptane

To a solution of the compound of step I (3.55 g, 14.36 mmol) in ethanol (150 mL) was added ammonium formate (2.71 g, 43.1 mmol) followed by palladium on activated carbon (10% palladium content, 456 mg, 4.3 mmol). The mixture was stirred at rt for 23 h and then filtered. The filtrate was concentrated on a rotary evaporator to give a secondary amine (1.62 g, 14.3 mmol, yield 100%).

To a solution of the aforementioned secondary amine in methanol (150 ml) was added benzaldehyde (1.6 ml, 15.8 mmol) and acetic acid (0.82 ml, 14 mmol) followed by sodium borohydride cyano sodium (1.6 g, 14 mmol). The mixture was stirred overnight at room temperature. The resulting solution was treated with HCl until the pH of the solution was about 3. A small amount of gas evolution was observed. The solvent was removed in vacuo and the residue was treated with aqueous K ₂ CO ₃ solution (pH> 10) and extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afford the title compound (2.7 g, 13.3 mmol, 93% yield).

¹ H NMR (CDCl ₃ ): 7.34 (m, 2H), 7.25 (m, 3H), 4.16 (m, 1H), 3.43 (d, J = 13.1 Hz, 1H), 3.36 (d, J = 13.1 Hz, 1H), 2.62 (d, J = 10.8 Hz, 1H), 2.52 (dd, J = 11.3 Hz, 5.3, 1H), 2.28 (dd, J = 11.8 Hz, 4.5, 1H), 2.14 (dd, J = 11.8 Hz, 4.6, 1H), 1.68 (bs, 1H), 1.38 (m, 1H), 1.24 (m, 1H), 0.64 (m, 1H), 0.52 (m, 1H).

3. 3-benzyl-3-azabicyclo [4.1.0] heptan-5-one

Oxalyl chloride (2.9 ml, 34 mmol) was added to a solution of dimethyl sulfoxide (4.8 ml, 68.5 mmol) in methylene chloride (150 ml) at -78 ° C. After 15 minutes, the compound of step 2 (3.4, 17 mmol) was added slowly at this temperature. The mixture was stirred at -78 ° C for 40 minutes. Triethylamine (14.32 ml, 102.8 mmol) was added to this solution. Stirring was continued for 5 minutes and then the reaction was allowed to warm to room temperature. The reaction mixture was poured into saturated sodium chloride solution and extracted with ethylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afford crude. This was purified by silica gel chromatography (eluent; 15% ethyl acetate / hexanes). The title compound was obtained as a viscous oil (2.23 g, 11.1 mmol, yield 65%).

¹ H NMR (CDCl ₃ ): 7.32-7.21 (m, 5H), 3.50 (d, J = 13.2 Hz, 1H), 3.42 (d, J = 13.2 Hz, 1H), 3.26 (d, J = 18.5 Hz, 1H), 3.09 (d, J = 11.1 Hz, 1H), 2.58 (d, J = 18.5 Hz, 1H), 2.45 (dd, J = 11.1, 1.3 Hz, 1H), 1.92 (c, J = 4.6 Hz, 1H), 1.79 (m, 1H), 1.69 (m, 1H), 1.06 (m, 1H).

4. 3-benzyl-3-azabicyclo [4.1.0] heptan-5-one oxime

A solution of step 3 compound (2.23 g, 11.1 mol) and hydroxylamine hydrochloride (1.0 g, 14.4 mmol) in 80% ethanol (110 ml) was stirred at reflux for 30 minutes. The solvent was removed in vacuo and the residue was dissolved in ether. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afford 3-benzyl-3-azabicyclo [4.1.0] heptan-5-one as a viscous yellow oil (2.28 g, 10.6 mmol, yield). 95%).

¹ H NMR (CDCl ₃ , mixture of two isomers): 8.75 (br m, 2H), 7.34-7.17 (m, 10H), 3.77 (d, J = 17.8 Hz, 1H), 3.47 (doublet, J = 13.2 Hz, 2H), 3.46 (dual line, J = 13.2 Hz, 2H), 3.43 (m, 1H), 3.15 (d, J = 14.0 Hz, 1H), 2.96 (d, J = 11.0 Hz, 1H), 2.73 ( d, J = 17.8 Hz, H), 2.67 (d, J = 14.0 Hz, 1H), 2.47 (dd, J = 11.0, 3.6 Hz, 1H), 2.31 (d, J = 11.0 Hz, 1H), 2.17 ( m, 1H), 1.71 (m, 1H), 1.43 (m, 2H), 1.36 (m, 1H), 1.05 (m, 1H), 0.99 (m, 1H), 0.76 (m, 1H).

5. [1α, 5α, 6α] -3-benzyl-5- (tert-butoxycarbonyl) amino-3-azabicyclo [4.1.0] heptane

To a solution of the compound of step 4 (2.28 g, 10.6 mmol) in tetrahydrofuran (50 ml) was added a solution of lithium aluminum hydride in tetrahydrofuran (60.6 mmol). The mixture was heated to reflux for 2 hours, cooled to room temperature and then quenched with ethyl acetate (11.6 ml), followed by water (2 ml), aqueous NaOH solution (15%, 6.9 ml) and water (6.9 ml). The resulting precipitate was filtered off and the filtrate was diluted with saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afford the title compound as a viscous yellow oil (1.95 g, 9.65 mmol, 91% yield). This was done without purification by one of the following two routes to afford the title compound.

a) by bicarbonate di-t-butyl and triethylamine

3-benzyl-5-amino-3-azabicyclo [4.1.0] heptane (1.95 g, 9.6 mmol) and di-t-butyl bicarbonate (2.3 g, 10.5 mmol) in dioxane (90 ml) and water (10 ml) To the solution of triethylamine (1.6 ml, 11.5 mmol) was added. The mixture was stirred at room temperature for 5 hours, diluted with saturated sodium bicarbonate solution and then extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to a yellow oil. This oil was chromatographed on silica gel (eluent; 30% ethyl acetate / hexanes) to give the title compound (1.3 g, 4.3 mmol, yield 45%) from a fraction with high Rf (Rf 0.82, 30% ethyl acetate / hexanes). ). Fractions with low Rf values (Rf 0.68, 30% ethyl acetate / hexanes) provided the [1α, 5β, 6α] isomer (0.56 g, 1.85 mmol, 19% yield).

¹ H NMR (CDCl ₃ ) for the title compound: 7.31-7.19 (m, 5H), 5.24 (d, J = 8.1 Hz, 1H), 3.92 (bs, 1H), 3.38 (d, J = 13.2 Hz, 1H ), 3.31 (d, J = 13.2 Hz, 1H), 2.95 (dd, J = 11.2, 7.6 Hz, 1H), 2.31 (d, J = 11.9 Hz, 1H), 2.13 (m, 2H), 1.41 (s , 9H), 1.09 (m, 1H), 0.95 (m, 1H), 0.63 (m, 1H), 0.26 (m, 1H).

¹ H NMR (CDCl ₃ ) for [1α, 5β, 6α] isomers: 7.30-7.20 (m, 5H), 4.70 (bd, 1H), 4.10 (m, 1H), 3.42 (d, J = 13.1 Hz, 1H), 3.34 (d, J = 13.1 Hz, 1H), 2.61 (m, 1H), 2.51 (m, 1H), 2.31 (dd, J = 11.9, 4.9 Hz, 1H), 2.11 (dd, J = 11.9 , 3.5 Hz, 1H), 1.40 (s, 9H), 1.31 (m, 1H), 1.17 (m, 1H), 0.47 (m, 2H).

b) by di-t-butyl bicarbonate and sodium hydroxide

Powder hydroxide in a solution of 3-benzyl-5-amino-3-azabicyclo [4.1.0] heptane (518 mg, 2.56 mmol) and di-t-butyl bicarbonate (671 mg, 3.58 mmol) in dioxane (15 ml). Sodium (143 mg) was added followed by water (5 ml). The mixture was stirred for 1 hour, diluted with water and then extracted with ether. The ether layer was washed with brine, dried over magnesium sulfate and evaporated to an off white solid which was chromatographed on silica gel (eluent; 30% ethyl acetate / hexanes) as a white solid to give the title compound (187 mg, 0.619 mmol, yield 24%), the [1α, 5β, 6α] isomer of the title product (144 mg, 0.477 mmol, yield 19%) and a mixture of the title compound and its isomer (263 mg, 0.87 mmol, 34% yield). Got it.

6. [1α, 5α, 6α] -5- (tert-butoxycarbonyl) amino-3-azabicyclo [4.1.0] heptane

To the solution of the title compound (1.3 g, 4.3 mmol) of step 5 in ethanol (50 ml) was added ammonium formate (0.81 g, 12.9 mmol) followed by palladium based on activated carbon (10% palladium content, 0.136 g, 1.29 mmol). The mixture was stirred at rt for 2 h and then filtered. The filtrate was concentrated in vacuo to afford the title compound as a white solid (830 mg, 3.9 mmol, 91% yield).

¹ H NMR (CD ₃ OD): 3.60 (m, 1H), 3.10 (dd, J = 13.1, 5.7 Hz, 1H), 2.83 (d, J = 13.1 Hz, 1H), 2.61 (dd, J = 13.1, 4.7 Hz, 1H), 2.27 (dd, J = 13.1, 7.1 Hz, 1H), 1.43 (s, 9H), 0.99 (m, 1H), 0.89 (m, 1H), 0.69 (m, 1H), 0.30 ( q, J = 5.4 Hz, 1H).

Example P

[1α, 5β, 6α] -5- (tert-butoxycarbonyl) amino-3-azabicyclo [4.1.0] heptane

To a solution of 2.64 mmol obtained as an isomer of Example 0.5 in ethanol (50 ml) was added ammonium formate (500 mg, 7.92 mmol) followed by palladium (10% palladium content, 837 mg, 0.79 mmol) based on activated carbon. The mixture was stirred at rt for 1.5 h and then filtered. The filtrate was concentrated in vacuo to afford 570 mg of the title compound as a yellow solid, such as beeswax (570 mg, recovered at least 100% by weight).

¹ H NMR (CDCl ₃ ): 4.80 (bm, 1H), 4.01 (m, 1H), 3.11 (m, 2H), 2.85 (m, 2H), 2.33 (m, 1H), 1.42 (s, 9H), 1.33 (m, 1 H), 1.19 (m, 1 H), 0.57 (m, 1 H), 0.45 (m, 1 H).

Example Q

1. [1α, 6α, 7α] -3-benzyloxycarbonyl-3-azabicyclo [4.1.0] heptan-7-carboxylic acid, ethyl ester

A solution of benzyl 1,2,5,6-tetrahydropyridine-1-carboxylate (20 g, 92 mmol) in methylene chloride (92 ml) was treated with rhodium acetate (1.2 g, 5.5 mmol). A solution of ethyl diazoacetate (31.5 g, 276 mmol) in methylene chloride (8.6 ml) was then added via syringe pump over 22 hours. After completion of the addition, the reaction mixture was filtered through Celite and the filtrate was concentrated to give the title compound which was used in step 2 without purification.

¹ H NMR (CDCl ₃ ): 7.32-7.23 (m, 5H), 5.09 (s, 2H), 4.08 (q, J = 7.3 Hz, 2H), 3.96 (d, J = 13.8 Hz, 1H), 3.55 ( dd, J = 13.8, 4.1 Hz, 1H), 3.45 (bm, 1H), 3.01 (m, 1H), 1.96 (m, 1H), 1.78-1.66 (bm, 3H), 1.45 (t, J = 4.3 Hz , 1H), 1.23 (t, J = 7.3 Hz, 3H).

2. [1α, 6α, 7α] -3-benzyloxycarbonyl-3-azabicyclo [4.1.0] heptan-7-carboxylic acid

The title compound of step 1 was dissolved in aqueous dioxane solution (20 vol%, 200 ml). Powdered sodium hydroxide (38 g) was added, then the mixture was stirred overnight at 85 ° C. After cooling to room temperature, the solution was extracted with ether. Sodium bisulfate was added to the aqueous layer, acidified to pH 2, and extracted with methylene chloride. The methylene chloride layers were washed with brine, dried over magnesium sulfate and concentrated to afford the title compound (13.09 g, 47.5 mmol, crude), which was used without purification in the next reaction step.

¹ H NMR (CDCl ₃ ): 7.32-7.23 (m, 5H), 5.09 (s, 2H), 3.96 (q, J = 13.8 Hz, 1H), 3.76 (m, 1H), 3.56 (dd, J = 13.8 , 3.9 Hz, 1H), 3.47 (m, 1H), 3.02 (m, 2H), 1.96 (m, 1H), 1.75 (m, 1H), 1.46 (t, J = 3.9 Hz, 1H).

3. [1α, 6α, 7α] -3-benzyloxycarbonyl-7- (tert-butoxycarbonyl) amino-3-azabicyclo [4.1.0] heptane

The mixture of step 2 compound (13.09 g, 47.5 mmol) and triethylamine (7.28 ml, 52.2 mmol) in acetone (150 ml) was cooled to 0 ° C. and ethyl chloroformate (5.4 ml, 57.0 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 30 minutes. Then a solution of sodium azide (30.85 g, 475 mmol) in water (70 ml) was added slowly. After an additional 2 hours, the mixture was diluted with water and then extracted with ether. The ether layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford azide acyl (7.90 g, 26.3 mmol, crude), which was used directly in the next reaction.

A solution of azide acyl in toluene (150 ml) was added dropwise to a toluene solution (150 ml) of t-butanol (30 ml) and pyridinium tosylate (9 mg) at 100 ° C. After the addition was completed, the reaction mixture was kept at 100 ° C. for 12 hours. The reaction mixture was concentrated in vacuo, then the residue was chromatographed on silica gel (eluant: 20% ethyl acetate / hexanes) to give the title compound as a viscous yellow oil (2.4 g, 6.9 mmol, benzyl 1,2, Yield 7.5% from 5,6-tetrahydropyridine-1-carboxylate).

¹ H NMR (CDCl ₃ ): 7.31 (m, 5H), 5.08 (s, 2H), 4.72 (bs, 1H), 3.88 (bd, J = 13.5 Hz, 1H), 3.62 (bm, 1H), 3.32 ( bm, 1H), 3.00 (bm, 1H), 2.27 (bm, 1H), 1.94 (m, 1H), 1.77 (m, 1H), 1.41 (s, 9H), 1.19 (m, 2H).

4. [1α, 6α, 7α] -7- (tert-butoxycarbonyl) amino-3-azabicyclo [4.1.0] heptane

To a solution of the mixture of step 3 (2.3 g, 6.6 mmol) in ethanol (100 mL) was added ammonium formate (1.24 g, 19.8 mmol) followed by palladium based on activated carbon (10% palladium content, 2.09 g, 1.9 mmol). The mixture was stirred at 60 ° C. for 1 h and overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as a viscous pale yellow oil (1.38 g, 6.51 mmol, 91% yield).

¹ H NMR (CD ₃ OD): 3.20 (dd, J = 13.2, 5.8 Hz, 1H), 2.97 (dd, J = 13.2, 1.5 Hz, 1H), 2.45 (m, 1H), 2.43 (m, 1H) , 2.33 (m, 1H), 1.92 (m, 1H), 1.72 (m, 1H), 1.43 (s, 9H), 1.11 (m, 1H), 1.03 (m, 1H).

The following examples illustrate the invention in detail.

Example 1

7- (3-Azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

A solution of 3-azabicyclo [3.1.0] hexyl hydrochloride (157 mg, 1.31 mmol) in dimethylsulfoxide (13 ml) (prepared in a similar manner as described in US Pat. No. 4, 183, 857) was prepared in 1- Treated with cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (348 mg, 1.31 mmol) and triethylamine (0.58 ml, 3.9 mmol) Then heated for 18 hours. The reaction mixture was filtered to give a white solid which was purified by column chromatography (eluent; 1% acetic acid in chloroform, then 5% acetic acid in chloroform, then methanol) to give the title product as a white solid (186 mg, 0.43 mmol, yield 33%). Melting point 290 ° C.

¹ H NMR (DMSO-d ₆ ): 8.54 (s, 1H), 7.75 (d, J = 14Hz, 1H), 7.08 (d, J = 9Hz, 1H), 3.83 (dd, J = 4.10Hz, 2H) , 3.73 (bs, 1H), 3.62 (bd, J = 10 Hz, 2H), 1.77 (m, 2H), 1.30 (d, J = 6 Hz, 2H), 1.14 (bs, 2H), 0.77 (m, 1H) , 0.30 (m, 1 H).

Example 2

A. 7- (1-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1, 4-Dihydro-4-oxo-quinoline-3-carboxylic acid

1-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hexane (0.30 g, 1.41 mmol) and triethylamine (0.39 ml, 2.8 mmol in acetonitrile (20 ml) ) Is treated with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (0.375 g, 1.41 mmol) and then at 50 ° C. Heated for 21 hours. The reaction mixture was then filtered to give the title product (508 mg, 1.11 mmol, yield 79%) as a white solid. Melting point 235.5 ° -236 ° C.

¹ H NMR (CDCl ₃ / CD ₃ OD): 8.62 (s, 1H), 7.84 (d, J = 14 Hz, 1H), 6.88 (d, J = 7 Hz, 1H), 5.06 (vbs, 1H), 3.84 ( m, 2H), 3.68 (m, 1H), 3.58 (m, 1H), 3.48 (m, 1H), 3.36 (bs, 2H), 1.64 (m, 1H), 1.45 (s, 9H), 1.36 (m , 2H), 1.17 (m, 2H), 0.87 (m, 1H), 0.66 (m, 1H).

B. 7- (1-Aminomethyl) -3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline- 3-carboxylic acid, hydrochloride

The title compound (442.8 mg, 0.97 mmol) of Example 2A was mixed with hydrochloric acid (3.0 ml of 6M solution) and acetic acid (3.0 ml) and then heated to 100 ° C. for 1 hour. The resulting solution was cooled, azeotropically distilled with toluene and concentrated in vacuo to give a yellow residue which was treated with isopropanol and then filtered. The title product (350 mg, 0.89 mmol, yield 92%) was obtained as a white solid. Melting point 261 ° C. (decomposition).

¹ H NMR (DMSO-d ₆ ): 8.57 (s, 1H), 7.79 (d, J = 13Hz, 1H), 7.11 (d, J = 7Hz, 1H), 4.00 (m, 1H), 3.81 (m, 1H), 3.71 (d, J = 9 Hz, 2H), 3.70 (m, 1H), 3.18 (d, J = 11 Hz, 1H), 3.06 (d, J = 11 Hz, 1H), 1.88 (m, 1H), 1.38 (bd, J = 7 Hz, 2H), 1.16 (bs, 2H), 1.06 (m, 1H), 0.68 (m, 1H).

Example 3

A. 7- (1-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6,8-difluoro -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

1-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hexane (501 mg, 2.35 mmol) and triethylamine (0.655 ml, 4.7 mmol) in acetonitrile (25 ml) ) Was heated to 80 ° C. for 24 h. The reaction mixture was then filtered to give the title product (851 mg, 1.79 mmol, yield 76%) as a white solid. Melting point 188 ° -189.5 ° C.

¹ H NMR (CDCl ₃ ): 14.6 (s, 1H), 8.72 (s, 1H), 7.80 (dd, J = 13, 2Hz, 1H), 4.67 (bs, 1H), 3.94 (m, 1H), 3.83 (d, J = 14, 6Hz, 1H), 3.76 (s, 2H), 3.66 (d, J = 10Hz, 1H), 3.42 (dd, J = 14, 6Hz, 1H), 3.29 (bdd, J = 14 , 6 Hz, 1H), 1.44 (bs, 10H), 1.24 (m, 2H), 1.12 (m, 2H), 0.70 (m, 2H).

B. 7- [1-Aminomethyl-3-azabicyclo [3.1.0] hex-3-yl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo- Quinoline-3-carboxylic acid, hydrochloride

The title compound (779.4 mg, 1.63 mmol) of Example 3B was mixed with hydrochloric acid (5.0 ml of 6M solution) and acetic acid (5.0 ml) and then heated to 100 ° C. for 1.75 h. The resulting solution was cooled, azeotropic distilled with toluene and concentrated in vacuo to give a residue, which was treated with isopropanol and then filtered. The title product (556 mg, 1.35 mmol, yield 83%) was obtained as a pale yellow solid. Melting point 251 ° C. (decomposition).

¹ H NMR (DMSO-d ₆ ): 8.63 (s, 1H), 7.74 (dd, J = 13, 2 Hz, 1H), 4.08 (m, 1H), 3.90 (d, J = 10 Hz, 1H), 3.70 ( m, 3H), 3.17 (d, J = 13 Hz, 1H), 3.03 (d, J = 13 Hz, 1H), 1.73 (m, 1H), 1.15 (m, 4H), 0.93 (m, 1H), 0.66 ( m, 1 H).

Example 4

A. 7- (1-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

1-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hexane (52.5 mg, 0.24 mmol) and triethylamine (66 μl, 0.48 mmol) in acetonitrile (3 ml) Is treated with 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (70 mg, 0.24 mmol) Heated to 80 ° C. for 20 h. The reaction mixture was then filtered to give the title product (89.0 mg, 0.19 mmol, yield 79%) as a white solid. Melting point 234 ° C. (decomposition).

¹ H NMR (CDCl ₃ ): 8.66 (s, 1H), 7.96 (d, J = 12Hz, 1H), 4.72 (bs, 1H), 4.11 (m, 2H), 3.80 (m, 2H), 3.58 (m , 1H), 3.36 (d, J = 6Hz, 2H), 1.60 (m, 1H), 1.43 (s, 9H), 1.22 (m, 2H), 1.02 (m, 2H), 0.88 (m, 1H), 0.58 (m, 1 H).

B. 7- [1-Aminomethyl-3-azabicyclo [3.1.0] hex-3-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 Naphthyridine-3-carboxylic acid, hydrochloride

The title compound (89 mg, 0.194 mmol) of Example 4A was mixed with hydrochloric acid (1.5 ml of 6M solution) and acetic acid (1.5 ml) and then heated to 100 ° C. for 1 hour. The resulting solution was cooled, then azeotropically distilled with toluene and concentrated in vacuo to afford a residue, which was treated with isopropanol and then filtered. The title product (48.4 mg, 0.122 mmol, yield 64%) was obtained as a pale yellow solid. Melting point 283 ° C. (decomposition).

¹ H NMR (DMSO-d ₆ ): 8.52 (s, 1H), 8.16 (bs, 1H), 7.95 (d, J = 13Hz, 1H), 4.18 (m, 1H), 4.02 (m, 1H), 3.86 (m, 2H), 3.66 (m, 1H), 3.08 (m, 2H), 1.86 (m, 1H), 1.24 (m, 2H), 1.06 (m, 3H), 0.61 (m, 1H).

Example 5

A. 7- (1-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-8- Methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

1-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hexane (209.6 mg, 0.99 mmol) and triethylamine (0.273 ml, 1.96) in dimethyl sulfoxide (10 ml) Millimoles) was treated with 0.82 mmol) and then heated to 80 ° C. for 42 hours. The reaction mixture was then concentrated in vacuo and the resulting solid was treated with isopropanol to give the title product (183 mg, 0.376 mol, yield 46%) as a white solid. Melting point 212 ° -213 ° C. (decomposition).

¹ H NMR (CDCl ₃ ): 8.79 (s, 1H), 7.79 (d, J = 13Hz, 1H), 4.69 (m, 1H), 3.99 (m, 1H), 3.66 (m, 4H), 3.57 (s , 3H), 3.48 (m, 1H), 3.27 (m, 1H), 1.58 (bs, 1H), 1.46 (s, 9H), 1.19 (m, 2H), 0.98 (m, 2H), 0.72 (m, 2H).

B. 7- [1-Aminomethyl-3-azabicyclo [3.1.0] hex-3-yl] -1-cyclopropyl-6-fluoro-8-methoxy-1, 4-dihydro-4- Oxo-quinoline-3-carboxylic acid

The title compound (166.7 mg, 0.34 mmol) of Example 5A was mixed with hydrochloric acid (2.5 ml of 6 M solution) and acetic acid (2.5 ml) and then heated to 100 ° C. for 3.5 hours. The resulting solution was cooled and then azeotropically distilled with heptane to give a residue, which was treated with isopropanol and ether. The product was then dissolved in water (2 ml), adjusted to pH 8.5 by addition of sodium hydroxide solution (0.1 N) and then filtered to give the title product (36.6 mg, 0.095 mmol, 28% yield) as a greenish solid. Got. Melting point 194 ° -196 ° C.

¹ H NMR (D ₂ O / NaOD): 8.50 (s, 1H), 7.62 (d, J = 14Hz, 1H), 4.05 (bs, 1H), 3.71 (d, J = 10Hz, 1H), 3.55 (s , 3H), 3.5 (m, 3H), 2.90 (bd, J = 13 Hz, 1H), 2.70 (bd, J = 13 Hz, 1H), 1.44 (bs, 1H), 1.11 (m, 2H), 0.90 (bs , 2H), 0.62 (m, 2H).

Example 6

A. 7- (1-[(N-acetyl) aminomethyl] -3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

A mixture of 1-[(N-acetyl) aminomethyl] -3-azabicyclo [3.1.0] hexane (115.5 mg 0.75 mmol) and triethylamine (312 μl, 2.25 mmol) in acetonitrile (20 ml) was added with 7-chloro Ethyl ester of -6-fluoro-1 (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (283 mg, 0.74 mmol) ) And then heated to 80 ° C. for 20 hours. Additional 1- (N-acetyl) -aminomethyl-3-azabicyclo [3.1.0] hexane (97 mg) was added in portions over 2.5 hours until thin layer chromatography indicated the absence of starting naphthyridine. The reaction mixture was concentrated in vacuo and then the residue was chromatographed on silica gel (eluent; 189: 10: 10 = chloroform: methanol: concentrated ammonium hydroxide). The title product (280.3 mg, 0.56 mmol, yield 76%) was obtained as a colorless oil.

¹ H NMR (CDCl ₃ ): 8.36 (s, 1H), 7.93 (d, J = 13Hz, 1H), 7.37 (bs, 1H), 7.07 (bs, 2H), 6.15 (bs, 1H), 4.36 (q , J = 7Hz, 2H), 3.48 (m, 6H), 2.02 (s, 3H), 1.50 (m, 1H), 1.37 (t, J = 7Hz, 3H), 0.81 (m, 1H), 0.43 (m , 1H).

B. 7- [1-Aminomethyl) -3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-di Hydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

Example 6A mixed the title compound (231.2 mg, 0.46 mmol) with hydrochloric acid (3 ml of 6M solution) and acetic acid (3 ml) and then heated to 100 ° C. for 24 hours. The resulting solution was cooled and then concentrated in vacuo to give a residue, which was mixed with isopropanol and isopropyl ether and filtered. The filtrate was concentrated and the product was treated with a small amount of cooled isopropanol to give a white solid which was dissolved in a minimal amount of sodium hydroxide solution and acidified with hydrochloric acid until a precipitate appeared. Filtration gave the title product as a yellow solid. Melting point 201 ° -203 ° C. (40 mg, 0.086 mmol, yield 19%).

¹ H NMR (D ₂ O / NaOD): 8.25 (s, 1H), 7.80 (d, J = 13Hz, 1H), 7.45 (m, 1H), 7.15 (m, 2H), 3.5 (vbm, 4H), 2.70 (bd, J = 13 Hz, 1H), 2.60 (bd, J = 13 Hz, 1H), 1.39 (bs, 1H), 0.68 (bs, 1H), 0.20 (bs, 1H).

Example 7

A. 7- (1- [N- (tert-butoxycarbonyl) ethylaminomethyl] -3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-quinoline-3-carboxylic acid

1- [N- (tert-butoxycarbonyl) ethylaminomethyl] -3-azabicyclo [3.1.0] hexane (45.3 mg, 0.18 mmol) and triethylamine (50 μl, 0.36 mmol in acetonitrile (5 ml) ) Was treated with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (50.0 mg, 0.18 mmol) and then up to 80 ° C. Heated for 18 hours. The reaction mixture was filtered to give the title product as a white solid (26.8 mg, 0.055 mmol, 31% yield).

¹ H NMR (CDCl ₃ ): 8.67 (s, 1H), 7.90 (d, J = 15Hz, 1H), 6.89 (d, J = 7Hz, 1H), 3.87 (bs, 2H), 3.5 (m, 5H) , 3.3 (bs, 2H), 1.6 (m, 1H), 1.49 (s, 9H), 1.33 (m, 2H), 1.14 (m, 5H), 0.83 (m, 1H), 0.68 (m, 1H).

B. 7- (1-Ethylaminomethyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline- 3-carboxylic acid, hydrochloride

The title compound (20.2 mg, 0.042 mmol) of Example 7A was mixed with hydrochloric acid (0.75 ml of 6 M solution) and acetic acid (0.75 ml) and then heated to 100 ° C. for 2 hours. The resulting solution is concentrated in vacuo, then the residue is treated with isopropanol and dried in vacuo to give the title product (11.2 mg, 0.027 mmol, 63% yield) as a yellow solid. Melting point 289 ° -293 ° C. (decomposition).

¹ H NMR (DMSO-d ₆ , 107 °): 8.6 (s, 1H), 7.85 (d, J = 14Hz, 1H), 7.2 (d, J = 7Hz, 1H), 4.05 (m, 1H), 3.75 (M, 4H), 3.3 (d, J = 10Hz, 1H), 3.2 (d, J = 10Hz, 1H), 2.9 (m, 2H), 1.95 (m, 1H), 1.45 (m, 2H), 1.3 (t, J = 7 Hz, 3H), 1.2 (m, 3H), 0.75 (m, 1H).

Example 8

A. 7- (1-acetylamino-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 Naphthyridine-3-carboxylic acid

A mixture of 1-acetylamino-3-azabicyclo [3.1.0] hexane (150 mg, 0.70 mmol) and triethylamine (0.48 ml, 3.5 mmol) in acetonitrile (7 ml) was added with 7-chloro-1-cyclopropyl Treated with -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (192.1 mg, 0.68 mmol) and then heated to 80 ° C. for 18 hours. The reaction mixture was filtered to give the title product (135.8 mg, 0.35 mmol, yield 51%) as a white solid. Melting point 275 ° C. (decomposition).

¹ H NMR (CDCl ₃ ): 8.55 (s, 1H), 8.49 (s, 1H), 7.96 (d, J = 18Hz, 1H), 4.22 (m, 1H), 3.98 (bs, 2H), 3.81 (m , 1H), 3.68 (m, 1H), 1.82 (bs, 4H), 1.12 (m, 5H), 0.78 (m, 1H).

B. 7- (1-Amino-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- Naphthyridine-3-carboxylic acid, hydrochloride

The title compound (133 mg, 0.34 mmol) of Example 8A was mixed with hydrochloric acid (2.5 ml of 6 M solution) and acetic acid (2.5 ml) and then heated to 100 ° C. for 18 hours. The resulting solution was cooled, azeotropically distilled with heptane and concentrated in vacuo to afford a residue, which was treated with isopropanol. The title product (114.7 mg, 0.30 mmol, yield 88%) was obtained as a yellow solid. Melting point 230 ° C. (decomposition).

¹ H NMR (DMSO-d ₆ ): 8.57 (s, 1H), 8.01 (d, J = 12Hz, 1H), 4.35 (m, 1H), 4.00 (m, 3H), 3.66 (bs, 1H), 2.15 (bs, 1H), 1.40 (m, 1H), 1.18 (m, 2H), 1.09 (bs, 2H), 0.91 (bs, 1H).

Example 9

A. 7- (1-acetylamino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid, ester

A mixture of 1-acetylamino-3-azabicyclo [3.1.0] hexane (60 mg, 0.28 mmol) and triethylamine (195 μl, 1.4 mmol) in acetonitrile (10 ml) was added with 7-chloro-6-fluoro- Treated with ethyl ester (95.6 mg, 0.25 mmol) of 1- (2,4-difluoro-phenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid Then heated to 80 ° C. for 20 hours. The reaction mixture was concentrated in vacuo, diluted with chloroform and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (eluent; 189: 10: 1 = chloroform: methanol: concentrated ammonium hydroxide) to give the title product as a yellow oil (120.8 mg, 0.25 mmol, 100% yield).

¹ H NMR (CDCl ₃ ): 8.35 (s, 1H), 8.01 (d, J = 13Hz, 1H), 7.36 (m, 1H), 7.04 (m, 2H), 6.11 (bs, 1H), 4.35 (q , J = 7 Hz, 2H), 3.96 (vbs, 1H), 3.69 (vbs, 3H), 1.96 (s, 3H), 1.73 (m, 1H), 1.37 (t, J = 7 Hz, 3H), 1.06 (m , 1H), 0.71 (m, 1H).

B. 7- (1-Amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1 (2,4-difluorophenyl) -1,4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

The title compound (116 mg, 0.24 mmol) of Example 9A was mixed with hydrochloric acid (3 mL of M solution) and acetic acid (3 mL) and then heated to 100 ° C. for 18 hours. The resulting solution was cooled and then concentrated in vacuo to give a residue, which was crystallized from ether / methanol. The resulting solid was dissolved in 0.5N sodium hydroxide solution and then filtered. Hydrochloric acid was then added to the filtrate and acidified until a precipitate appeared. The resulting mixture was filtered to give the title product (31.2 mg, 0.069 mmol, yield 29%) as a tan solid. Melting point 205 ° C. (decomposition).

¹ H NMR (D ₂ O / NaOH): 8.26 (s, 1 H), 7.76 (d, J = 13 Hz, 1 H), 7.42 (m, 1 H), 7.15 (m, 2 H), 3.82 (vbs, 1 H), 3.4 (vbm, 3H), 1.41 (bs, 1H), 0.86 (m, 1H), 0.29 (bs, 1H).

Example 10

A. 7-([1α, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl- 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 5α, 6α] -6-[(tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hexane (75 mg, in acetonitrile (10 ml) and triethylamine (2 ml) 0.35 mmol) of the ethyl ester of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (105 mg, 0.34 mmol) and then heated to 80 ° C. for 18 hours. The solvent was removed in vacuo to give a residue, which was column chromatographed (eluent: chloroform, then 5% methanol in chloroform) to give the title product (132 mg, 0.27 mmol, 79% yield).

¹ H NMR (CDCl ₃ ): 8.41 (s, 1H), 7.98 (d, J = 13Hz, 1H), 4.7 (bs, 1H), 4.35 (q, J = 7Hz, 2H), 4.08 (bd, J = 11 Hz, 2H), 3.72 (bd, J = 11 Hz, 2H), 3.45 (bs, 1H), 3.10 (m, 2H), 1.55 (bs, 2H), 1.40 (s, 9H), 1.36 (t, J = 7 Hz, 3H), 1.15 (m, 2H), 0.98 (bs, 2H), 0.90 (bs, 1H).

B. 7-([1α, 5α, 6α] -6-aminomethyl-3-azabicyclo [3.1.0] hex-3-yl) -cyclopropyl-6-fluoro-1,4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

The title compound (110 mg, 0.23 mmol) of Example 10A was dissolved in hydrochloric acid (6N, 6 ml) and acetic acid (6 ml) and then heated to reflux for 18 hours. The solvent was then removed in vacuo and the residue was recrystallized from acetonitrile-methanol. The title product (27 mg, 0.068 mmol, yield 30%) was obtained as pure white needle crystals. Melting point 272 ° C. (decomposition).

¹ H NMR (D ₂ O, 93 °): 9.5 (s, 1H), 8.6 (d, J = 14Hz, 1H), 5.0 (bd, J = 10Hz, 2H), 4.7 (bd, J = 10Hz, 2H ), 4.5 (bs, 1H), 3.8 (d, J = 6 Hz, 2H), 2.7 (bs, 2H), 2.1 (m, 2H), 1.8 (bs, 3H).

Example 11

A. 7- [1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

Solution of [1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (149 mg, 0.75 mmol) in acetonitrile (25 ml) and triethylamine (3 ml) Was treated with ethyl ester (230 mg, 0.74 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid Then heated to 80 ° C. for 15 hours. The solvent was removed in vacuo to give a residue, which was subjected to column chromatography (eluent: chloroform) to give a material which was treated with diethyl ether to give the title product (206 mg, 0.45 mmol, yield 60%). .

¹ H NMR (CDCl ₃ ): 8.46 (s, 1H), 8.04 (d, J = 13Hz, 1H), 4.80 (bs, 1H), 4.37 (q, J = 7Hz, 2H), 4.17 (bd, J = 11 Hz, 2H), 3.81 (bd, J = 11 Hz, 2H), 3.46 (m, 1H), 2.38 (bs, 1H), 1.89 (bs, 2H), 1.45 (s, 9H), 1.39 (t, J = 7 Hz, 3H), 1.18 (m, 2H), 0.99 (m, 2H).

B. 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid, dihydrochloride

The title compound (170 mg, 0.37 mmol) of Example 11.A was dissolved in hydrochloric acid (6N, 10 ml) and then heated to reflux for 24 hours. The solvent was then removed in vacuo and the residue was recrystallized from acetonitrile methanol. The title product (52 mg, 0.12 mmol, yield 34%) was obtained as a pale yellow solid. Melting point 180 deg. C (decomposition).

¹ H NMR (Methanol-d ₄ ): 8.65 (s, 1H), 7.93 (d, J = 13 Hz, 1H), 4.3 (bm, 2H), 3.98 (bm, 2H), 3.72 (bs, 1H), 2.68 (bs, 1H), 2.26 (bs, 2H), 1.30 (bs, 2H), 1.12 (bs, 2H).

Example 12

A. 7-([1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1 (2,4- Difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

A solution of [1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (200 mg, 1.01 mmol) in acetonitrile (35 ml) and triethylamine (5 ml) Ethyl ester of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ( 385 mg, 1.01 mmol) and then heated to 90 ° C. for 18 hours. The solvent was removed in vacuo to give a residue, which was partitioned between ethyl acetate and water. The organic layer was treated with activated charcoal, filtered and concentrated, then the residue was column chromatographed (eluent; 5% methanol in chloroform). The material so obtained was recrystallized from diethyl ether to give the title product (296 mg, 0.54 mmol, yield 54%). Melting point 256 ° -258 ° C.

¹ H NMR (CDCl ₃ ): 8.35 (s, 1H), 8.06 (d, J = 13Hz, 1H), 7.37 (m, 1H), 7.05 (m, 2H), 4.72 (vbs, 1H), 4.37 (q , J = 7 Hz, 2H), 3.81 (vbs, 2H), 3.55 (bm, 2H), 2.26 (bs, 1H), 1.78 (bs, 2H), 1.43 (s, 9H), 1.38 (t, J = Hz , 2H).

B. 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

The title compound (250 mg, 0.46 mmol) of Example 12.A was dissolved in hydrochloric acid (6N, 20 ml) and then heated to reflux for 24 hours. The solvent was then removed in vacuo, then the residue was treated with acetonitrile, washed with diethyl ether and then recrystallized from acetonitrile methanol. The title product (116 mg, 0.26 mmol, yield 57%) was obtained as a pale yellow solid. Melting point 246 ° C. (decomposition).

¹ H NMR (Methanol-d ₄ ): 8.68 (s, 1 H), 7.96 (d, J = 13 Hz, 1 H), 7.57 (m, 1 H), 7.22 (m, 1 H), 7.14 (m, 1 H), 3.82 (vbs, 2H), 3.62 (vbs, 2H), 2.37 (bs, 1H), 2.03 (bs, 2H).

Example 13

A. 7-([1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4 -Difluorophenyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, ethyl ester

[1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (210 mg, 1.06 mmol) in dimethyl sulfoxide (20 ml) and triethylamine (5 ml) Solution of 6,7-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (365 mg, 1.0 mmol) Was heated to 80 ° C. for 60 h. After the solvent was removed in vacuo, the residue was purified by column chromatography (eluent: chloroform). The title product (432 mg, 0.79 mmol, yield 79%) was obtained as a yellow foam.

¹ H NMR (CDCl ₃ ): 8.23 (s, 1H), 7.96 (d, J = 15Hz, 1H), 7.43 (m, 1H), 7.14 (m, 2H), 5.65 (d, J = 6.9Hz, 1H ), 4.73 (bs, 1H), 4.34 (d, J = 7 Hz, 2H), 3.68 (m, 2H), 3.36 (m, 2H), 2.31 (s, 1H), 1.78 (s, 2H), 1.40 ( s, 9H), 1.36 (t, J = 7 Hz, 3H).

B. 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1 (2,4-difluorophenyl)- 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, mesylate salt

The suspension of the compound of Example 13.A (400 mg, 0.73 mmol) in dioxane (25 ml) and water (25 ml) was treated with methanesulfonic acid (0.25 ml, 3.8 mmol) and then heated at 100 ° C. for 18 hours. . The solvent was removed in vacuo, then the residue was dissolved in acetone, treated with activated charcoal and filtered through Celite. The filtrate was treated with ether to give the title product (108 mg, 0.22 mmol, yield 30%) as a pale yellow powder. Melting point 256 ° C. (decomposition).

¹ H NMR (MeOD-d ₄ / D ₂ O): 8.62 (s, 1H), 7.85 (d, J = 13Hz, 1H), 7.71 (m, 1H), 7.35 (m, 2H), 5.90 (m, 1H), 3.74 (m, 2H), 3.47 (m, 2H), 2.45 (bs, 1H), 2.13 (s, 2H).

Example 14

A. 10-([1α, 5α6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hex-3-yl) -9-fluoro-2,3-dihydro-3 -Methi-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid

[1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (75 mg, 0.38 mmol) in dimethyl sulfoxide (6 ml) and triethylamine (1 ml) 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid (100 mg, 0.36 mmol) was heated to 80 ° C. for 72 hours. The solvent was removed in vacuo, then the residue was partitioned between chloroform and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield a yellow powder. This was further purified by column chromatography (eluent; 50: 50: 1 = chloroform: methanol: concentrated ammonium hydroxide) to give the title product (98 mg, 0.21 mmol, yield 59%) as a yellow solid. Melting point 170 ° -173 ° C. (decomposition).

¹ H NMR (CDCl ₃ ): 8.60 (s, 1H), 7.68 (d, J = 13Hz, 1H), 4.77 (bs, 1H), 4.48 (m, 2H), 4.33 (bd, J = 12Hz, 1H) , 3.96 (m, 2H), 3.71 (m, 2H), 2.64 (bs, 1H), 1.77 (s, 2H), 1.62 (d, J = 7 Hz, 3H), 1.48 (s, 9H).

B. 10-[(1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl] -9-fluoro-2,3-dihydro-3-methyl-7 -Oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid, hydrochloride

A solution of the compound of Example 14.A (85 mg, 0.19 mmol) in 6N hydrochloride (5 ml) was stirred at room temperature for 2 hours. After the solvent was removed in vacuo, the residue was recrystallized from acetonitrile-methanol-ether to give the title product (48 mg, 0.12 mmol, yield 63%) as a solid. Melting point 186 ° -188 ° C. (decomposition).

¹ H NMR (D ₂ O): 8.62 (s, 1H), 7.07 (d, J = 13.3 Hz, 1H), 4.55 (bd, J = 11 Hz, 1H), 4.38 (bd, J = 10 Hz, 1H), 3.96 (dd, J = 14.2, 9.8Hz, 2H), 3.69 (dd, apparent t, J = 10Hz, 2H), 2.77 (s, 1H), 2.09 (s, 2H), 1.57 (d, J = 6.8Hz , 3H).

Example 15

A. 7-([1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hex-3-yl) -5-amino-1-cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

[1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (115 mg, 0.58 mmol) in dimethyl sulfoxide (3 ml) and triethylamine (0.3 ml) And suspension of 5-amino-1-cyclopropyl-6,7.8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (125 mg, 0.42 mmol) at 80 ° C. Heated for hours. The solvent was removed in vacuo, then the residue was partitioned between methylene chloride and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give the title product (146 mg, 0.31 mmol, yield 74%).

¹ H NMR (CDCl ₃ ): 8.58 (s, 1H), 4.71 (bs, 1H), 3.90 (m, 3H), 3.69 (d, J = 9.8 Hz, 2H), 2.52 (s, 1H), 1.75 ( s, 2H), 1.43 (s, 9H), 1.15 (m, 2H), 1.00 (bs, 2H).

B. 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -5-amino-1-cyclopropyl-6,8-difluoro- 1,4-dihydro-4-oxo-quinolyl-3-carboxylic acid, methanesulfonate

A solution of the compound of Example 15.A (135 mg, 0.28 mmol) and methanesulfonic acid (28 μl, 0.41 mmol) in dioxane (20 ml) and water (20 ml) was heated to 100 ° C. for 18 hours. After removal of the solvent, the residue was dissolved in methanol and isopropanol, treated with activated charcoal and then filtered through Celite. The resulting filtrate was partially concentrated in vacuo to give a powder which was collected by filtration to give the title product (57 mg, 0.12 mmol, 43% yield). Melting point> 275 ° C.

¹ H NMR (MeOD-d ₄ ): 8.52 (s, 1H), 3.96 (m, 1H), 3.94 (d, J = 10.5Hz, 2H), 3.71 (d, J = 9.7Hz, 2H), 2.68 ( s, 3H), 2.04 (s, 2H), 1.15 (m, 2H), 1.09 (bs, 2H).

Example 16

A. 7-([1α, 2β, 5α, 6α] -6-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro- 1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 2β, 5α, 6α] -6-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hexane (370 mg) in acetonitrile (50 ml) and triethylamine (5 ml) , 1.74 mmol) and 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid A solution of ethyl ester (600 mg, 1.57 mmol) of ethyl ester was heated to reflux for 18 hours. The solvent was removed in vacuo and the residue was column chromatographed (eluent: chloroform) to give the title product (345 mg, 0.62 mmol, yield 39%) as an oil.

Mixture of ¹ H NMR (CDCl ₃ ) Rotamers: 8.35 and 8.33 (s, 1H), 8.03 and 8.01 (d, J = 12.5 Hz, 1H), 7.38 (m, 1H), 7.02 (m, 2H), 4.73 (bs, 1H), 4.33 (q, J = 7 Hz, 2H), 3.99 (m, 2H), 3.58 (m, 1H), 2.39 (s, 1H), 1.77 (m, 2H), 1.40 (s, 9H ), 1.34 (t, J = 7.4 Hz, 3H), 1.00 and 0.88 (d, J = 5.7 Hz, 3H).

B. 7-([1α, 2β, 5α, 6α] -6-amino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4 -Difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate

A solution of the compound of Example 16.A (0.30 g, 0.53 mmol) and methanesulfonic acid (0.10 ml, 1.53 mmol) in acetonitrile (30 ml) and water (15 ml) was heated to reflux for 24 hours. The solvent was removed in vacuo and the residue was recrystallized from methanol-acetonitrile and then isopropanol-ether to give the title product (56 mg, 0.11 mol, 21% yield) as a white solid. Melting point> 275 ° C. (photosensitive at 208 ° C.).

¹ H NMR (MeOD-d ₆ , 87 ° C.): 8.79 (s, 1H), 8.11 (d, J = 12.6 Hz, 1H), 7.79 (dt, J = 5.9, 8.7 Hz, 1H), 7.52 (ddd, J = 10.3, 9.0, 2.7 Hz, 1H), 7.33 (m, 1H), 4.10 (m, 1H), 3.96 (dd, J = 11, 5 Hz, 1H), 3.83 (m, 1H), 2.58 (m, 1H), 2.34 (s, 3H), 2.15 (m, 2H), 0.96 (m, 3H).

Example 17

A. 7-([1α, 2β, 5α, 6α] -6-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl- 6-Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

[1α, 2β, 5α, 6α] -6-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hexane in dimethylsulfoxide (5 ml) and triethylamine (0.5 ml) 135 mg, 0.64 mmol) and a solution of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (120 mg, 0.45 mmol) at 80 ° C. Heated for 18 h. The solvent was removed in vacuo, then the residue was dissolved in ethyl acetate (100 ml), treated with activated charcoal, filtered through Celite and then concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-ether to give the title product (137 mg, 0.30 mmol, yield 67%). Melting point 214 ° -216 ° C. (decomposition).

¹ H NMR (CDCl ₃ ): 8.70 (s, 1H), 7.94 (d, J = 13.5Hz, 1H), 7.08 (d, J = 7.3Hz, 1H), 4.73 (bs, 1H), 4.21 (m, 2H), 3.44 (m, 2H), 2.61 (s, 1H), 1.98 (m, 1H), 1.85 (m, 1H), 1.44 (s, 9H), 1.36 (s, J = 5.6 Hz, 3H), 1.32 (m, 1 H), 1.20 (m, 2 H), 1.13 (m, 1 H).

B. 7-([1α, 2β, 5α, 6α] -6-amino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-quinoline-3-carboxylic acid, methanesulfonate

A suspension of the compound of Example 17.A (130 mg, 0.28 mmol) and methanesulfonic acid (0.03 ml, 0.44 mmol) in acetonitrile (10 ml) and water (10 ml) was heated to reflux for 18 hours. After the solvent was removed in vacuo, the residue was recrystallized from isopropanol-methanol to give the title product (38 mg, 0.084 mmol, yield 30%) as a white solid. Melting point> 275 ° C.

¹ H NMR (DMSO-d ₆ ): 8.65 (s, 1H), 8.14 (bs, 1H), 7.89 (d, J = 13.4Hz, 1H), 7.33 (d, J = 7.7Hz, 1H), 4.29 ( m, 1H), 4.08 (m, 1H), 3.78 (m, 1H), 3.42 (m, 1H), 2.71 (s, 1H), 2.29 (s, 3H), 2.23 (m, 1H), 2.10 (m , 1H), 1.29 (d, J = 5.5 Hz, 3H), 1.25 (m, 3H), 1.11 (m, 1H).

Example 18

A. 7-([1α, 2β, 5α, 6α] -6-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -5-amino-1 -Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

[1α, 2β, 5α, 6α] -6-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hexane in dimethyl sulfoxide (1 ml) and triethylamine (0.1 ml) 65 mg, 0.31 mmol) and 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (80 mg, 0.27 mmol ) Was heated at 85 ° C. for 18 hours. Further 3-azabicyclo [3.1.0] hexane (10 mg, 0.047 mmol) was added and heating continued for 16 h. The solvent was removed in vacuo, then the residue was partitioned between chloroform and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give the title product (51 mg, 0.10 mmol, yield 37%).

¹ H NMR (CDCl ₃ ): 8.62 (s, 1H), 6.44 (vbs, 2H), 4.66 (bs, 1H), 4.30 (m, 1H), 3.94 (m, 2H), 3.31 (dd, J = 9.2 , 3.6 Hz, 1H), 2.70 (s, 1H), 1.72 (m, 2H), 1.44 (s, 9H), 1.19 (m, 3H), 1.16 (d, J = 5.9 Hz, 3H), 0.98 (m , 1H).

B. 7-([1α, 2β, 5α, 6α] -6-amino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -5-amino-1-cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, methanesulfonate

A solution of the compound of Example 18.A (48 mg, 0.098 mmol) and methanesulfonic acid (15 μl, 0.21 mmol) in dioxane (3 ml) and water (3 ml) was heated to 100 ° C. for 24 h. After removal of the solvent, the residue was treated with isopropanol to give the title product (32 mg, 0.066 mmol, yield 67%) as a solid. Melting point> 275 ° C.

¹ H NMR (DMSO-d ₆ ): 8.52 (s, 1H), 8.11 (m, 2H), 4.20 (m, 1H), 4.02 (m, 1H), 3.79 (d, J = 9.6Hz, 1H), 3.36 (m, 1H), 2.61 (bs, 1H), 2.31 (s, 3H), 2.05 (m, 1H), 1.98 (m, 1H), 1.11 (m, 5H), 1.02 (m, 2H).

Example 19

A. 7-([1α, 2β, 5α] -1-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 2β, 5α] -1-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hexane (122 mg) in dimethyl sulfoxide (3 ml) and triethylamine (0.3 ml) , 0.57 mmol) and 7-chloro-6-fluoro-1 (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl A solution of ethyl ester (208 mg, 0.54 mmol) of ester was heated at 85 ° C. for 3.5 hours. The solvent was removed in vacuo, then the residue was partitioned between chloroform and water. The organic layer was dried over sodium sulfate, then concentrated and the resulting material was purified by column chromatography (eluent: chloroform) to give the title product (217 mg, 0.39 mmol, 72% yield) as a white solid. Melting point 254 ° C. (decomposition).

¹ H NMR (CDCl ₃ ): 8.33 (m, 1H), 8.05 (bd, J = 12 Hz, 1H), 7.30 (m, 1H), 6.99 (m, 2H), 4.90 (bs, 1H), 4.37 (q , J = 7 Hz, 2H), 3.90 (m, 2H), 3.73 (m, 1H), 1.81 (m, 1H), 1.43 (s, 9H), 1.40 (t, J = 7 Hz, 3H), 0.88 (m , 2H).

B. 7-([1α, 2β, 5α] -6-amino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-di Fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methylsulfonate

A solution of the compound of Example 19.A (190 mg, 0.34 mmol) and methanesulfonic acid (50 μl, 0.73 mmol) in dioxane (10 ml) and water (10 ml) was heated to reflux for 19 hours. The solvent was removed in vacuo, then the residue was dissolved in methanol-isopropanol and treated with activated charcoal. Concentration in vacuo gave the title product (59 mg, 0.14 mmol, yield 40%) as a solid. Melting point> 275 ° C.

¹ H NMR (DMSO-d ₆ ), mixture of rotamers: 8.91 and 8.87 (s, 1H), 8.19 and 8.18 (d, J = 12.5 Hz, 1H), 7.83 (m, 1H), 7.60 (m, 1H ), 7.37 (m, 1H), 3.99 (m, 1H), 3.86 (m, 2H), 2.30 (s, 3H), 2.08 (m, 1H), 1.18 (m, 1H), 1.05, and 0.88 (d, J = 6.0 Hz, 3H), 0.96 (m, 3H).

Example 20

A. 7-([1α, 2β, 5α] -1-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6- Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 2β, 5α] -1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (130 mg, 0.61 mmol in dimethyl sulfoxide (3.5 ml) and triethylamine (0.3 ml) ) And ethyl ester (180 mg, 0.58 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester ) Suspension was heated at 80 ° C. for 26 h. The solvent was removed in vacuo, then the residue was chromatographed (eluent: chloroform) and then recrystallized from ether. The title product (96 mg, 0.20 mmol, yield 34%) was obtained as a yellow solid. Melting point 181 ° -183 ° C.

¹ H NMR (CDCl ₃ ): 8.48 (s, 1H), 8.06 (d, J = 12.3 Hz, 1H), 5.06 (bs, 1H), 4.42 (q, J = 5.9 Hz, 1H), 4.36 (q, J = 7 Hz, 2H), 4.08 (dd, J = 10.4, 5.5 Hz, 1H), 3.84 (m, 1H), 3.49 (m, 1H), 1.92 (m, 1H), 1.42 (s, 9H), 1.40 (m, 6 H). 1.18 (m, 2 H), 1.03 (m, 4 H).

B. 7-([1α, 2β, 5α] -1-amino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4 -Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate

A solution of the compound of Example 20.A (80 mg, 0.16 mmol) and methanesulfonic acid (11 μl, 0.17 mmol) in dioxane (10 ml) and water (10 ml) was heated to reflux for 42 hours. The solvent was removed in vacuo and the residue was treated with acetone and then recrystallized from isopropanol-methanol. The title product (33 mg, 0.073 mmol, yield 46%) was obtained as a solid. Melting point> 275 ° C.

¹ H NMR (DMSO-d ₆ ): 8.64 (s, 1H), 8.13 (d, J = 13.0 Hz, 1H), 4.64 (bq, J = 5.9 Hz, 1H), 3.97 (m, 2H), 3.72 ( m, 1H), 2.30 (s, 3H), 2.17 (m, 1H), 1.50 (d, J = 5.9 Hz, 3H), 1.16 (m, 6H).

Example 21

A. 7-([1α, 2β, 5α] -1-[(N-acetyl) aminomethyl] -2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro- 1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 2β, 5α] -1-[(N-acetyl) aminomethyl] -2-methyl-3-azabicyclo [3.1.0] hexane (101 mg, 0.60 mmol) and triethyl in acetonitrile (15 ml) A mixture of amines (0.25 ml, 1.8 mmol) was added to 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine Treatment with ethyl ester of -3-carboxylic acid (206 mg, 1.8 mmol) was followed by heating to 80 ° C. for 24 h. The reaction mixture was concentrated in vacuo and then chromatographed on a chromatotron using a silica gel plate (eluent; 89: 10: 1 = chloroform: methanol: concentrated ammonium hydroxide) to give the title product (244 mg, 0.47 mmol, Yield 87%).

¹ H NMR (CDCl ₃ , mixture of rotifiers): 8.40 and 8.35 (s, 1H), 7.96 (bd, J = 12.4 Hz, 1H), 7.23 (m, 3H), 5.91 (bs, 1H), 4.34 ( q, J = 7 Hz, 2H), 3.86 (m, 2H), 3.71 (m, 1H), 3.57 (m, 1H), 3.20 and 2.96 (m, 1H), 2.03 and 1.97 (s, 3H), 1.54 ( m, 1H), 1.36 (t, J = 7 Hz, 3H), 0.90 and 0.74 (d, J = 5.7 Hz, 3H), 0.67 (m, 1H), 0.57 (m, 1H).

B. 7-([1α, 2β, 5α] -1-aminomethyl-3-methyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4- Difluorophenyl) -1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acid, hydrochloride

Example 21.A compound (232 mg, 0.45 mmol) was mixed with hydrochloric acid (3 ml of 6N solution) and acetic acid (3 ml) and then heated to 100 ° C. for 7 days. The reaction mixture was then concentrated in vacuo and the residue was treated with isopropanol to give the title product (90.1 mg, 0.19 mmol, yield 42%) as a cream solid. Melting point 239 ° C. (decomposition).

¹ H NMR (DMSO-d ₆ , 87 ° C.): 8.75 (s, 1 H), 8.09 (d, J = 12.9 Hz, 1 H), 7.80 (m, 1 H), 7.52 (m, 1 H), 7.33 (m, 1H), 4.14 (m, 1H), 3.85 (dd, J = 11.0, 4.8 Hz, 1H), 3.75 (m, 1H), 3.21 (d, J = 13.9 Hz, 1H), 2.79 (d, J = 13.9 Hz, 1H), 1.94 (m, 1H), 0.98 (d, J = 5.8 Hz, 3H), 0.91 (dd, J = 8.4, 5.4 Hz, 1H), 0.72 (dd, apparent t, J = 4.9 Hz, 1H).

Example 22

A. 7-([1α, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro -1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl) -3-azabicyclo [3.1.0] hexane (307 mg, 1.45 mmol) and acetonitrile (40 ml) A mixture of ethylamine (8 ml) was added to 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3- Treated with ethyl ester of carboxylic acid (525 mg, 1.37 mmol) and then heated to 80 ° C. for 18 hours. The solvent was removed in vacuo, then the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting material was stopped by chromatography on silica gel (eluant: chloroform) to give the title product as a foam (608 mg, 1.12 mmol, 77% yield).

¹ H NMR (CDCl ₃ ,): 8.32 (s, 1H), 8.00 (d, J = 12.9Hz, 1H), 7.37 (m, 1H), 7.03 (m, 2H), 4.66 (bs, 1H), 4.33 (q, J = Hz, 2H), 3.69 (m, 2H), 3.45 (m, 2H), 3.02 (m, 2H), 1.49 (s, 2H), 1.40 (s, 9H), 1.35 (t, J = 7 Hz, 3H), 0.77 (m, 1H).

B. 7-([1α, 5α, 6α] -6-aminomethyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl ) -1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acid, hydrochloride

Example 22. A compound (600 mg, 1.1 mmol) was treated with hydrochloric acid (25 mL of 6N solution) and then heated to reflux for 18 hours. The solvent was removed to give a solid which was recrystallized from methanol and then washed with ether to give the title product (186 mg, 0.398 mmol, yield 36%) as a white solid. Melting point> 275 ° C. (186 mg, 0.398 mmol, yield 36%).

¹ H NMR (D ₂ O, 87 ° C.): 9.40 (s, 1 H), 8.63 (d, J = 12.8 Hz, 1H), 8.24 (m, 1H), 7.94 (m, 2H), 4.48 (m, 2H ), 4.28 (m, 2H), 3.66 (d, J = 7.2 Hz, 2H), 2.45 (s, 2H), 1.59 (s, 1H).

Example 23

A. 7-([1α, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl -6-Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, ethyl ester

[1α, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hexane in dimethylsulfoxide (8 ml) and triethylamine (1 ml) 350 mg, 1.6 mmol) of ethyl ester of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (as in Example 22.A) 352 mg, 1.2 mmol) gave the title product (296 mg, 0.61 mmol, yield 51%) as a solid. Melting point 135 ° -137 ° C.

¹ H NMR (CDCl ₃ ): 8.43 (s, 1H), 7.93 (d, J = 14.9 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 4.69 (bs, 1H), 4.35 (q, J = 6.8 Hz, 2H), 3.82 (dd, J = 9.9, 2.9 Hz, 2H), 3.48 (m, 2H), 3.32 (m, 1H), 3.08 (m, 2H), 1.61 (s, 2H), 1.43 (s, 9H), 1.37 (t, J = 7 Hz, 3H), 1.25 (m, 2H), 1.08 (m, 2H), 1.00 (m, 1H).

B. 7-([1α, 5α, 6α] -6-aminomethyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro 4-oxo-quinoline-3-carboxylic acid, hydrochloride

The compound of Example 23.A (225 mg, 0.46 mmol) was converted to the method of Example 22.B to give the title product (146 mg, 0.39 mmol, yield 85%) as a yellow solid. Melting point> 275 ° C.

¹ H NMR (MeOD-d ₄ ): 8.57 (s, 1H), 7.66 (d, J = 14.7Hz, 1H), 7.05 (d, J = 7.7Hz, 1H), 3.96 (bd, J = 7Hz, 2H ), 3.69 (bd, J = 9 Hz, 2H), 2.97 (d, J = 7.6 Hz, 2H), 1.92 (s, 2H), 1.39 (m, 2H), 1.20 (m, 3H).

Example 24

A. 10-([1α, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl) -3-azabicyclo [3.1.0] hex-3-yl) -9-fluoro -2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3, -de] -1,4-benzoxazine-6-carboxylic acid

[1α, 5α, 6α] -1-([N-tert-butoxycarbonyl] aminomethyl) -3-azabicyclo [3.1.0] hexane (300) in dimethyl sulfoxide (5 ml) and triethyl (1 ml) Mg, 1.58 mmol) and 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine A mixture of -6-carboxylic acid (260 mg, 0.92 mmol) was treated as in Example 22.A to give the title product (96 mg, 0.22 mmol, yield 24%).

¹ H NMR (CDCl ₃ ): 8.54 (s, 1H), 7.67 (d, J = 13.1 Hz, 1H), 4.60 (bs, 1H), 4.41 (m, 2H), 4.28 (m, 1H), 3.80 ( m, 2H), 3.63 (m, 2H), 3.08 (m, 2H), 1.58 (d, J = 6.4 Hz, 3H), 1.54 (s, 2H), 1.43 (s, 9H), 1.10 (m, 1H ).

B. 10 [(1α, 5α, 6α) -6-aminomethyl-3-azabicyclo [3.1.0] hex-3-yl] -9-fluoro-2,3-dihydro-3-methyl-7 -Oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid, methylsulfonate

The suspension of the compound of Example 24.A (80 mg, 0.17 mmol) in acetone (2.5 ml) and water (2.5 ml) was treated with methanesulfonic acid (0.10 ml, 1.5 mmol) and then heated in a steam bath for 1.5 h. I was. The solvent was removed in vacuo and the residue was treated with acetone to give the title product (38 mg, 0.08 mmol, 47% yield) as a yellow solid. Melting point 276 ° C. (decomposition).

¹ H NMR (D ₂ O): 8.66 (s, 1H), 7.18 (d, J = 13.6Hz, 1H), 4.78 (m, 1H), 4.57 (m, 1H), 4.37 (m, 1H), 3.91 (m, 2H), 3.67 (m, 2H), 3.03 (d, J = 7.3 Hz, 2H), 2.82 (s, 3H), 1.73 (s, 2H), 1.58 (d, J = 6.1 Hz, 3H) , 1.27 (m, 1 H).

Example 25

A. 7-([1α, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro -1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, ethyl ester

[1α, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl] -3-azabicyclo [3.1.0] hexane in dimethyl sulfoxide (5 ml) and triethylamine (1 ml) 225 mg, 1.06 mmol) was added as ethyl ester of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid as in Example 22.A. 356 mg, 1.0 mmol) gave the title product as a foam (226 mg, 0.406 mmol, yield 41%).

¹ H NMR (CDCl ₃ ): 8.22 (s, 1H), 7.96 (d, J = 13Hz, 1H), 7.45 (m, 1H), 7.12 (m, 2H), 5.67 (bd, J = Hz, 1H) , 4.60 (bs, 1H), 4.37 (q, J = 7 Hz, 2H), 3.60 (m, 2H), 3.32 (m, 2H), 3.05 (m, 2H), 1.55 (s, 2H) 1.45 (s, 9H), 1.40 (t, J = 7 Hz, 3H), 0.92 (m, 1H).

B. 7-([1α, 5α, 6α] -6-aminomethyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl ) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, methanesulfonate

The compound of Example 25.A (200 mg, 0.35 mmol) was treated with methanesulfonic acid (95 liters, 1.43 mmol) as in Example 24.B to give the title product (82 mg, 0.16 mmol, 44% yield as 44% yellow powder). ) Melting point 255 ° C. (decomposition).

¹ H NMR (D ₂ O, 97 ° C.): 9.43 (s, 1H), 8.47 (m, 2H), 8.16 (m, 2H), 6.64 (m, 1H), 4.39 (m, 2H), 4.24 (m , 2H), 3.79 (m, 2H), 3.57 (s, 3H), 2.60 (s, 2H), 1.80 (m, 1H).

Example 26

A. 7-([1α, 2β, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl] -2-methyl-3-azivicyclo [3.1.0] hex-3- Yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 2β, 5α, 6α] -6-[(N-tert-butoxycarbonyl) aminomethyl] -2-methyl-3-azabicyclo [3.1.0] hexane (400 mg) in acetonitrile (50 ml) , 1.75 mmol) and triethylamine (5 ml) were prepared by 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-di by the method of Example 22.A. Treatment with ethyl ester (625 mg, 1.63 mmol) of hydro-4-oxo-1,8-naphthyridine-3-carboxylic acid gave the title product (687 mg, 1.2 mmol, 74% yield).

¹ H NMR (mixture of CDCl ₃ , rotamer): 8.35 and 8.34 (s, 1H) m 8.04 and 8.02 (d, J = 12.5 Hz, 1H), 7.38 (m, 1H), 7.03 (m, 2H), 4.63 (bs, 1H), 4.33 (q, J = 7 Hz, 2H), 3.95 (m, 2H), 3.53 (m, 1H), 2.99 (m, 2H), 1.55 (m, 2H), 1.41 (s, 9H), 1.35 (t, J = 7 Hz, 3H), 0.94 (m, 1H), 0.91 and 0.79 (d, J = 5.9 Hz, 3H).

B. 7-([1α, 2β, 5α, 6α] -6-aminomethyl-2-methyl--3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2 , 4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

The compound of Example 26.A (650 mg, 1.13 mmol) was converted as in Example 22.B to afford the title product (78 mg, 0.16 mmol, 14% yield).

¹ H NMR (MeOD-d ₄ , mixture of rotamers): 8.73 and 8.71 (s, 1H), 8.00 (d, J = 12 Hz, 1H), 7.57 (m, 1H), 7.22 (m, 2H), 4.02 (m, 2H), 3.70 (m, 1H), 2.87 (m, 2H), 1.83 (m, 2H), 1.11 (m, 1H), 0.96 and 0.85 (d, J = 6 Hz, 3H).

Example 27

A. 7-([1α, 5α, 6α] -6-tert-butoxycarbonyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid, ethyl ester

[1α, 5α, 6α] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (275 mg, 1.38 mmol) in dimethyl sulfoxide (10 ml) and triethylamine (2 ml), and A suspension of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (335 mg, 1.14 mmol) was treated as in Example 22.A. The title product was obtained as a solid (261 mg, 0.625 mmol, yield 55%). Melting point 202 ° -204 ° C.

¹ H NMR (CDCl ₃ ): 8.44 (s, 1H), 7.93 (d, J = 13Hz, 1H), 6.78 (d, J = 6Hz, 1H), 4.80 (bs, 1H), 4.40 (q, J = 7 Hz, 2H), 3.91 (m, 2H), 3.55 (bd, J = 8 Hz, 2H), 3.31 (m, 1H), 2.45 (s, 1H), 1.88 (s, 2H), 1.45 (s, 9H) , 1.39 (t, J = 7 Hz, 3H), 1.25 (m, 2H), 1.09 (m, 2H).

B. 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-quinoline-3-carboxylic acid, hydrochloride

The compound of Example 27.A (200 mg, 0.48 mmol) was treated as in Example 22.B to obtain the title product (64.6 mg, 0.17 mmol, yield 35%) as a solid. Melting point 202 ° -204 ° C. (decomposition).

¹ H NMR (D ₂ O, 87 ° C.): 9.23 (s, 1 H), 8.08 (d, J = 14.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 4.62 (dd, J = 10.6 , 2.9 Hz, 2H), 4.37 (bd, J = 10.7 Hz, 2H), 4.25 (m, 1H), 3.38 (s, 1H), 3.01 (s, 2H), 2.09 (m, 2H), 1.81 (m , 2H).

Example 28

A. 7-([1α, 2α, 5α] -1-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 2α, 5α] -1-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hexane and 7-chloro-6-fluoro-1- (2,4-di Fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is reacted according to the method of Example 23.A and purified to give the title product as a solid. Got. Melting point 181 ° -183 ° C. (72% yield).

¹ H NMR (MeOH-d ₄ ): 8.57 (s, 1H), 7.96 (bd, J = 12.4 Hz, 1H), 7.63 (m, 1H), 7.26 (m, 2H), 4.3 (vbm, 1H), 4.28 (q, J = 7.0 Hz, 2H), 3.8 (vbm, 2H), 1.72 (m, 1H), 1.42 (s, 9H), 1.31 (t, J = 7.0 Hz, 3H), 0.98 (m, 4H ), 0.65 (m, 1 H).

B. 7-([1α, 2α, 5α] -1-amino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-di Fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate

7-([1α, 2α, 5α] -1-tert-butoxycarbonylamino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1 (2, 3-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester was hydrolyzed to the title product by the method of Example 25.B. . The product was purified by recrystallization from acetone to give a solid. Melting point> 275 ° C. (yield 82%).

¹ H NMR (D ₂ O, 67 ° C.): 9.30 (s, 1H), 8.39 (d, J = 12.4 Hz, 1H), 8.08 (m, 1H), 7.79 (m, 2H), 4.96 (m, 1H ), 4.37 (m, 2H), 3.30 (s, 3H), 2.64 (m, 1H), 1.81 (m, 1H), 1.69 (bs, 3H), 1.33 (m, 1H).

Example 29

A. 7-([1α, 5α, 6α] -6-[(N-methyl) -tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl -6-Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

[1α, 5α, 6α] -6- [N-methyl) -tert-butoxycarbonylamino] -3-azabicyclo [3.1.0] hexane and -1-cyclopropyl-6,7-difluoro- 1,4-Dihydro-4-oxo-quinoline-3-carboxylic acid was reacted according to the method of Example 18.A. Purification by recrystallization from ethyl acetate gave the title product as a solid. Melting point 253 ° -256 ° C. (yield 40%).

¹ H NMR (CDCl ₃ ): 8.66 (s, 1H), 7.90 (d, J = 14.3 Hz, 1H), 6.89 (d, J = 7.3 Hz, 1H), 3.97 (m, 2H), 3.72 (bd, J = 9.2 Hz, 2H), 3.48 (m, 1H), 2.89 (s, 3H), 2.43 (m, 1H), 2.05 (bs, 2H), 1.50 (s, 9H), 1.35 (m, 2H), 1.18 (m, 2 H).

B. 7-([1α, 5α, 6α] -6-[(N-methyl) amino-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-quinoline-3-carboxylic acid, methanesulfonate

The compound of Step A was hydrolyzed according to the method of Example 25.B. Recrystallization from isopropanol-methanol gave the title product as a solid. Melting point 275 ° C. (yield 46%).

¹ H NMR (DMSO-d ₆ ): 8.75 (bs, 1H), 8.59 (s, 1H), 7.83 (d, J = 14.5 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 3.91 ( m, 2H), 3.70 (m, 3H), 2.73 (s, 1H), 2.68 (s, 3H), 2.30 (s, 3H), 2.26 (s, 2H), 1.28 (m, 2H), 1.15 (m , 2H).

Example 30

A. 7-([1α, 5α, 6α] -6-[(N-methyl) -tert-butoxycarbonylamino] -3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro Rho-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 5α, 6α] -6- (N-methyl) -tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane and 7-chloro-6-fluoro-1- (2,4 Ethyl ester of -difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was reacted according to the method of Example 22.A. After removing the reaction solvent, purification was carried out by recrystallization from ethyl acetate / ether to give the title product as a white solid. Melting point 171 ° -173 ° C. (84% yield).

¹ H NMR (CDCl ₃ ): 8.37 (s, 1H), 8.06 (d, J = 12.7Hz, 1H), 7.39 (m, 1H), 7.06 (m, 2H), 4.38 (q, J = 7.1Hz, 2H), 3.82 (vbm, 2H), 3.60 (vbm, 2H), 2.83 (s, 3H), 2.21 (m, 1H), 1.86 (bs, 2H), 1.45 (s, 9H), 1.39 (t, J = 7.1 Hz, 3H).

B. 7-([1α, 5α, 6α] -6-[(N-methyl) amino] -3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2, 4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate

The compound of Step A was hydrolyzed according to the method of Example 25B. Recrystallization from acetone-methanol gave the title product as off-white powder. Melting point> 275 ° C. (yield 53%).

¹ H NMR (D ₂ O, 77 ° C.): 9.35 (s, 1 H), 8.35 (d, J = 13 Hz, 1H), 8.15 (m, 2H), 7.90 (m, 2H), 4.45 (d, J = 8 Hz, 2H), 4.25 (d, J = 8 Hz, 2H), 3.45 (s, 3H), 3.40 (s, 3H), 3.20 (s, 1H), 2.90 (s, 2H).

Example 31

A. 7-([1α, 5α, 6β] -6-[-tert-butoxycarbonylamino] -3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- ( 2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 5α, 6β] -6- (tert-butoxycarbonylamino) -3-azabicyclo [3.1.0] hexane and 7-chloro-6-fluoro-1- (2,4-difluoro Ethyl ester of phenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was reacted according to the method of Example 22.A. After removal of the reaction solvent, the residue was partitioned between chloroform and water. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the material, which was then recrystallized from ethyl acetate to give the title product as a white solid. Melting point 248 ° C. (decomposition) (72% yield).

¹ H NMR (CDCl ₃ ): 8.33 (s, 1H), 8.00 (d, J = 12.5 Hz, 1H), 7.36 (m, 1H), 7.02 (m, 2H), 4.51 (bs, 1H), 4.34 ( q, J = 7 Hz, 2H), 3.67 (bm, 2H), 3.56 (bm, 2H), 2.75 (m, 1H), 1.86 (bs, 2H), 1.36 (m, 12H).

B. 7-([1α, 5α, 6β] -6-amino-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate

The compound of Step A was hydrolyzed according to the method of Example 25.B. The resulting powder was treated with acetone to give a white powder. Melting point> 275 ° C. (yield 77%).

¹ H NMR (D ₂ O-MeOH-d ₄ ): 8.76 (s, 1 H), 7.85 (d, J = 12.0 Hz, 1 H), 7.55 (m, 1 H), 7.21 (m, 2H), 3.85 (m , 4H), 2.84 (t, J = 7.4 Hz, 1H), 2.72 (s, 3H), 2.08 (bd, J = 7.5 Hz, 2H).

Example 32

A. 7-([1α, 5α, 6β] -6- [tert-butoxycarbonylamino] -3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 5α, 6β] -6- (tert-butoxycarbonylamino) -3-azabicyclo [3.1.0] hexane and 7-chloro-1-cyclopropyl-6-fluoro-1,4-di Ethyl ester of hydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was reacted according to the method of Example 22.A. After removal of the reaction solvent, the residue was partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the material, which was then purified by chromatography (eluant: 5% methanol in chloroform) to afford the title product as a solid. Melting point 226 ° -228 ° C. (decomposition) (yield 94%).

¹ H NMR (CDCl ₃ ): 8.44 (s, 1H), 8.01 (d, J = 12.8Hz, 1H), 4.59 (bs, 1H), 4.35 (q, J = 7Hz, 2H), 3.93 (m, 4H ), 2.86 (m, 1H), 1.96 (m, 2H), 1.36 (m, 12H), 1.16 (m, 2H), 0.98 (m, 2H).

B. 7-([1α, 5α, 6β] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate

The compound of Step A was hydrolyzed according to the method of Example 25.B. The resulting material was treated with acetone to give a white powder. Melting point> 275 ° C. (yield 88%).

¹ H NMR (D ₂ O): 8.47 (s, 1H), 7.73 (d, J = 12.3Hz, 1H), 4.16 (s, 4H), 3.65 (m, 1H), 2.96 (t, J = 7.5Hz , 1H), 2.73 (s, 3H), 2.23 (d, J = 7.5 Hz, 2H), 1.27 (m, 2H), 1.02 (m, 2H).

Example 33

A. 7-([1α, 2β, 5α, 6α] -6-tert-butoxycarbonylamino] -2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl -6-Fluoro-1,4-dihydro-4-oxo1,8-naphthyridine-3-carboxylic acid, ethyl ester

[1α, 2β, 5α, 6α] -6- (tert-butoxycarbonylamino) -2-methyl-3-azabicyclo [3.1.0] hexane and 7-chloro-1-cyclopropyl-6-fluoro The ethyl ester of -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was reacted according to the method of Example 20.A. The title product was obtained as a solid. Melting point 206 ° -209 ° C. (decomposition) (yield 65%).

¹ H NMR (CDCl ₃ ): 8.47 (s, 1H), 8.05 (d, J = 12.9Hz, 1H), 4.71 (bs, 1H), 4.55 (m, 1H), 4.35 (d, J = 7.4Hz, 2H), 4.20 (m, 1H), 3.68 (m, 1H), 3.48 (m, 1H), 2.55 (s, 1H), 1.95 (m, 1H), 1.86 (m, 1H), 1.47 (d, J) = 5.9 Hz, 3H), 1.44 (s, 9H), 1.37 (t, J = 7.4 Hz, 3H), 1.18 (m, 2H), 1.01 (m, 2H).

B. 7-([1α, 2β, 5α, 6α] -6-amino-2-methyl-3-azabicyclo [3.1.0] hex-3-yl) -1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate

The compound of Step A was hydrolyzed according to the method of Example 25.B. The material obtained in this way was crystallized with acetone to give the title product as a solid. Melting point> 289 ° C. (76% yield).

¹ H NMR (D ₂ O): 8.52 (s, 1H), 7.49 (d, J = 12.4Hz, 1H), 4.65 (m, 1H), 4.15 (m, 1H), 3.96 (m, 1H), 3.61 (m, 1H), 2.79 (m, 4H), 2.42 (m, 1H), 2.33 (m, 1H), 1.48 (d, J = 5.7 Hz, 3H), 1.29 (m, 2H), 1.05 (m, 2H).

Example 34

A. 7- (1-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

A solution of 1-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptane (200 mg, 0.94 mmol) and ethyl ester (327 mg, 0.85 mmol) in acetonitrile (12 ml) was heated for 3 hours It was refluxed. The solvent was removed in vacuo and the residue was chromatographed on silica gel (eluant: 50% ethyl acetate / hexanes) to give the title product as an off-white solid (423 mg, 0.758 mmol, 88% yield).

¹ H NMR (CDCl ₃ ): 8.33 (s, 1H), 8.02 (d, J = 13Hz, 1H), 7.33 (m, 1H), 7.01 (m, 2H), 4.83 (bs, 1H), 4.35 (q , J = 7 Hz, 2H), 4.11 (bd, J = 13 Hz, 1H), 3.52 (bm, 2H), 3.09 (bm, 1H), 1.99 (bm, 1H), 1.58 (bm, 1H), 1.40 (s , 9H), 1.35 (t, J = 7 Hz, 3H), 0.78 (dd, J = 12.6 Hz, 1H), 0.42 (t, J = 4 Hz, 1H).

B. 7- (1-Amino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

A solution of the compound of step A (300 mg, 0.54 mmol) in ethyl acetate (6 ml) and 3N hydrochloric acid (6 ml) was heated to reflux overnight. The solvent was removed in vacuo and the residue was recrystallized from methanol-acetonitrile to give the title product (155.5 mg, 0.338 mmol, yield 62%) as a white solid. Melting point 192 ° C. (decomposition).

¹ H NMR (DMSO-d ₆ ): 8.86 (s, 1 H), 8.16 (d, J = 13.7 Hz, 1 H), 7.80 (m, 1 H), 7.60 (m, 1 H), 7.34 (m, 1 H), 4.04 (dd, J = 13.8, 8.2 Hz, 1H), 3.87 (dd, J = 13.8, 9.2 Hz, 1H), 3.40 (m, 1H), 3.18 (m, 1H), 1.97 (m, 1H), 1.46 (m, 2H), 1.10 (m, 1H), 0.64 (m, 1H).

Example 35

A. 7- (1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4- Oxo-quinoline-3-carboxylic acid

According to the method of Example 34.A, 1-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptane (270.0 mg, 1.27 mmol) and 1-cyclopropyl-6,7-difluoro -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (275.6 mg, 1.03 mmol) gave the title compound (304.2 mg, 0.606 mmol, 65%).

¹ H NMR (CDCl ₃ ): 8.70 (s, 1H), 7.93 (d, J = 13.3 Hz, 1H), 7.28 (m, 1H), 5.03 (bs, 1H), 3.82 (m, 1H), 3.46 ( m, 3H), 3.19 (bm, 1H), 2.24 (bm, 1H), 1.93 (bm, 1H), 1.63 (bm, 1H), 1.43 (s, 9H), 1.37 (m, 2H), 1.16 (bs , 2H), 0.94 (dd, J = 9.7, 5.5 Hz, 1H), 0.80 (t, J = 6.0 Hz, 1H).

B. 7- (1-Amino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- Carboxylic acid, hydrochloride

The compound of step A (287.2 mg, 0.63 mmol) was converted using hydrochloric acid according to the method of step 34B to give the title compound (152.4 mg, 0.387 mmol, 62% yield). Melting point 235 ° C.

Example 36

A. 7- (1-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1 , 4-dihydro-4-oxo-quinoline-3-carboxylic acid, ether ester

According to the method of Example 34A, 1-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptane (270.0 mg, 1.27 mmol) and 6,7-difluoro-1- (2,4 Difluorophenyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, ethyl ester (463.6 mg, 1.27 mmol) were reacted with the title compound (333.3 mg, 0.59 mmol, yield 47%. )

¹ H NMR (CDCl ₃ ): 8.24 (s, 1H), 7.92 (d, J = 14Hz, 1H), 7.54 (m, 1H), 7.13 (m, 2H), 6.03 (m, 1H), 4.99 (bs , 1H), 4.31 (q, J = 7 Hz, 2H), 3.46 (m, 1H), 3.14 (m, 2H), 2.86 (m, 1H), 2.09 (bm, 1H), 1.77 (m, 1H), 1.38 (m, 13 H), 0.84 (dd, J = 9, 6 Hz, 1 H), 0.71 (m, 1 H).

B. 7- (1-Amino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro- 4-oxo-quinoline-3-carboxylic acid, hydrochloride

According to the method of Example 34B, the compound of step B (333.3 mg, 0.59 mmol) was converted with hydrochloric acid to give the title product (128.5 mg, 0.276 mmol, 47% yield). Melting point 223 ° C. (decomposition).

¹ H NMR (DMSO-d ₆ ): 8.84 (s, 1 H), 7.98 (d, J = 13.5 Hz, 1 H), 7.93 (m, 1 H), 7.75 (m, 1 H), 7.46 (m, 1 H), 6.22 (d, J = 7.3 Hz, 1H), 3.62 (d, J = 12.3 Hz, 1H), 3.40 (dd, J = 12.3 Hz, 1H), 3.15 (m, 1H), 2.93 (m, 1H), 2.10 (m, 1H), 1.63 (m, 1H), 1.52 (m, 1H), 1.14 (dd, J = 10.4, 5.7 Hz, 1H), 0.71 (m, 1H).

Example 37

A. 7-([1α, 5α, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4 -Difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

According to the method of Example 34A, [1α, 5α, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptane (122 mg, 0.57 mmol) and 7-chloro-6- Ethyl ester (218 mg, 0.57 mmol) of fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid Reaction gave the title product (205 mg, 0.367 mmol, yield 64%).

¹ H NMR (CDCl ₃ ): 8.36 (s, 1H), 8.09 (d, J = 13.8 Hz, 1H), 7.37 (m, 1H), 7.05 (m, 2H), 4.75 (m, 1H), 4.36 ( q, J = 7 Hz, 2H), 3.87 (m, 2H), 3.46 (m, 2H), 320 (m, 1H), 1.43 (s, 9H), 1.36 (t, J = 7 Hz, 3H), 1.08 ( m, 2H), 0.73 (m, 1H), 0.24 (m, 1H).

B. 7-([1α, 5α, 6α] -5-amino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

According to the method of Example 34B, the compound of Step A was converted using hydrochloric acid to give the title product (50.1 mg, 0.11 mmol, yield 40%). Melting point 200 ° -210 ° C. (decomposition).

¹ H NMR (D ₂ O): 8.83 (bs, 1H), 7.88 (bm, 1H), 7.60 (bm, 1H), 7.29 (bm, 2H), 3.9-3.6 (m, 5H), 1.38 (bm, 1H), 1.24 (bm, 1H), 0.92 (bm, 1H), 0.42 (bm, 1H).

Example 38

A. 7-([1α, 5α, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

Example 34A According to this method, [1α, 5α, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptane (150 mg, 0.7 mmol) and 7-chloro-1- Ethyl ester of cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (217.3 mg, 0.7 mmol) was reacted to give the title product (230 Mg, 0.47 mmol, yield 67%).

¹ H NMR (CDCl ₃ ): 8.47 (s, 1H), 8.06 (d, J = 13.2 Hz, 1H), 5.33 (bs, 1H), 4.35 (q, J = 7.3 Hz, 2H), 4.20 (m, 1H), 4.11 (m, 1H), 3.79 (m, 2H), 3.55-3.35 (m, 2H), 1.41 (s, 9H), 1.37 (t, J = 7.3 Hz, 3H), 1.21 (m, 4H ), 0.98 (m, 2H), 0.81 (m, 1H), 0.34 (m, 1H).

B. 7-([1α, 5α, 6α] -5-amino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate

According to the method of Example 34B, step A converts compound (220 mg, 0.45 mmol) with methanesulfonic acid in dioxane (15 ml) and water (15 ml) to give the title compound (153.8 mg, 0.339 mmol, 75% yield. ) Melting point> 260 ° C.

¹ H NMR (D ₂ O): 8.58 (s, 1H), 7.72 (d, J = 12.6Hz, 1H), 4.33 (bm, 1H), 4.08-3.84 (m, 5H), 2.81 (s, 3H) , 1.55 (m, 1 H), 1.33 (bs, 3 H), 1.07 (bs, 3 H), 0.60 (bs, 1 H).

Example 39

A. 7-([1α, 5α, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-1,8-quinoline-3-carboxylic acid

[1α, 5α, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptane (187.8 mg, 0.88 mmol) and 1-cyclopropyl-6, according to the method of Example 34A , 7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (210 mg, 0.79 mmol) was reacted to give the title product (195 mg, 0.426 mmol, yield 48%). . Melting point 167 ° C.

B. 7-([1α, 5α, 6α] -5-amino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-quinoline-3-carboxylic acid, hydrochloride

According to the method of Example 34B, the compound of Step A (195 mg, 0.43 mmol) was converted using hydrochloric acid to give the title product (113.4 mg, 0.289 mmol, 67% yield). Melting point 210 ° C. (decomposition).

¹ H NMR (D ₂ O): 8.53 (bs, 1H), 7.47 (m, 2H), 4.00 (bs, 1H), 3.88 (m, 1H), 3.68-3.40 (m, 3H), 3.21 (m, 1H), 1.62 (m, 1H), 1.44 (m, 2H), 1.37 (m, 1H), 1.18 (m, 2H), 1.09 (m, 1H), 0.73 (m, 1H).

Example 40

A. 7-([1α, 5α, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6,8-difluoro Rho-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

[1α, 5α, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptanes (200 mg, 0.94 mmol) and 1-cyclopropyl-6, according to the method of Example 34A , 7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (313 mg, 0.94 mmol) was reacted to give the title product (290 mg, 0.61 mmol, yield 65 %).

¹ H NMR (CDCl ₃ ): 8.74 (s, 1H), 7.84 (d, J = 11.6Hz, 1H), 4.98 (m, 1H), 4.04 (m, 1H), 3.93 (m, 1H), 3.70 ( dd, J = 12.3, 5.6 Hz, 1H), 3.40 (d, J = 12.3 Hz, 1H), 3.32 (m, 1H), 2.89 (m, 1H), 1.39 (s, 9H), 12.4 (m, 2H ), 1.12 (m, 2H), 1.04 (m, 1H), 0.79 (m, 1H), 0.51 (m, 1H), 0.29 (m, 1H).

B. 7-([1α, 5α, 6α] -5-amino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6,8-difluoro-1,4- Dihydro-4-oxo-quinoline-3-carboxylic acid, methanesulfonate

According to the method of Example 34B, the compound of step A (290 mg, 0.61 mmol) was converted to methanesulfonic acid in dioxane (10 ml) and water (10 ml) to give the title product (51.1 mg, 0.11 mmol, 18% yield). Got it. Melting point> 250 ° C.

¹ H NMR (D ₂ O-NaOH): 8.50 (s, 1H), 7.66 (d, J = 12.4 Hz, 1H), 4.01 (m, 1H), 3.68 (m, 1H), 3.45 (d, J = 11.6 Hz, 1H), 3.30 (d, J = 11.6 Hz, 1H), 3.22 (m, 1H), 2.83 (s, 3H), 2.79 (m, 1H), 1.23 (m, 2H), 1.10 (m, 2H), 0.98 (m, 1H), 0.74 (m, 1H), 0.46 (m, 1H), 0.22 (m, 1H).

Example 41

A. 7-([1α, 5α, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -5-amino-1-cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

According to the method of Example 34A, [1α, 5β, 6α] -1-5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptanes (110 mg, 0.52 mmol) and 5-amino- 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (140 mg, 0.46 mmol) was reacted in dimethyl sulfoxide to give the title product ( 220 mg, 0.45 mmol, yield 98%) was obtained.

¹ H NMR (DMSO-d ₆ ): 8.48 (s, 1H), 7.25 (bs, 1H), 7.10 (d, J = Hz, 1H), 4.00 (m, 1H), 3.72 (m, 1H), 3.61 (bd, J = 10Hz, 1H), 3.47 (d, J = 12Hz, 1H), 2.76 (t, J = 10Hz, 1H), 1.38 (s, 9H), 1.16 (m, 1H), 0.97 (m, 1H), 0.69 (m, 1H), 0.35 (m, 1H).

B. 7-([1α, 5α, 6α] -5-amino-3-azabicyclo [4.1.0] hept-3-yl) -5-amino-1-cyclopropyl-6,8-difluoro- 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, hydrochloride

According to the method of Example 34B, the compound of step A (220 mg, 0.45 mmol) was converted using hydrochloric acid to give the title product (76.5 mg, 0.18 mmol, 40% yield). Melting point> 238 ° C.

¹ H NMR (DMSO-d ₆ / D ₂ O): 8.50 (s, 1H), 3.99 (m, 1H), 3.62 (m, 1H), 3.47 (m, 2H), 3.01 (m, 2H), 1.32 (m, 1H), 1.07 (m, 5H), 0.81 (m, 1H), 0.53 (m, 1H).

Example 42

A. 7-([1α, 5β, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4 -Difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

According to the method of Example 34A, [1α, 5β, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptane (212 mg, 1.0 mmol) and 7-chloro-6- Ethyl ester (363.3 mg, 0.95 mmol) of fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid Reaction gave the title product (389 mg, 0.70 mmol, yield 73%).

¹ H NMR (CDCl ₃ ): 8.35 (s, 1H), 8.08 (d, J = 13Hz, 1H), 7.35 (m, 1H), 7.05 (m, 2H), 4.58 (m, 1H), 4.36 (q , J = 7Hz, 2H), 4.05 (m, 1H), 3.80 (m, 1H), 3.45 (m, 1H), 3.30 (m, 1H), 1.44 (bs, 10H), 1.38 (t, J = 7Hz , 3H), 1.22 (m, 1H), 0.54 (m, 1H), 0.26 (m, 1H).

B. 7-([1α, 5β, 6α] -5-amino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

According to the method of Example 34B, the compound of Step A (383.4 mg, 0.68 mmol) was converted with hydrochloric acid to give the title product (173.1 mg, 0.377 mmol, 55% yield). Melting point> 200 ° C.

¹ H NMR (D ₂ O): 8.85 (s, 1H), 7.95 (d, J = 12.8Hz, 1H), 7.60 (m, 1H), 7.32 (m, 2H), 4.03 (m, 1H), 3.96 -3.73 (m, 2H), 3.53 (m, 2H), 1.55 (m, 1H), 1.46 (m, 1H), 0.84 (m, 1H), 0.56 (m, 1H).

Example 43

A. 7-([1α, 5β, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-quinoline-3-carboxylic acid

[1α, 5β, 6α] -5-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptanes (133 mg, 0.62 mmol) and 1-cyclopropyl-6, according to the method of Example 34A , 7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (164 mg, 0.62 mmol) was reacted to give the title product (99.6 mg, 0.218 mmol, 35% yield). .

¹ H NMR (CDCl ₃ ): 8.72 (s, 1H), 7.96 (d, J = 13.3Hz, 1H), 7.38 (d, J = 7.2Hz, 1H), 4.82 (bd, J = 7.6Hz, 1H) , 4.28 (m, 1H), 3.58 (m, 3H), 3.30 (m, 1H), 3.12 (m, 1H), 1.44 (m, 13H), 1.15 (m, 2H), 0.71 (m, 1H), 0.62 (m, 1 H).

B. 7-([1α, 5β, 6α] -5-amino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-quinoline-3-carboxylic acid, hydrochloride

According to the method of Example 34B, the compound of Step A (99 mg, 0.21 mmol) was converted using hydrochloric acid to give the title product (32 mg, 0.081 mmol, 38% yield). Melting point 252 ° C. (decomposition).

¹ H NMR (DMSO-d ₆ ): 8.71 (s, 1H), 8.39 (bs, 2H), 7.97 (d, J = 13Hz, 1H), 7.62 (bs, 1H), 4.0-3.2 (m, 6H) , 1.57 (m, 2H), 1.41 (m, 2H), 12.4 (m, 2H), 1.00 (m, 1H), 0.81 (m, 1H).

Example 44

A. 7-([1α, 6α, 7α] -7-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4 -Difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

According to the method of Example 34A, [1α, 6α, 7α] -7-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptane (300 mg, 1.41 mmol) and ethyl ester (535.3 mg, 1.40 mmol) was reacted to give the title product (780 mg, 1.39 mmol, 99%).

¹ H NMR (CDCl ₃ ): 8.40 (s, 1H), 8.12 (d, J = 13Hz, 1H), 7.43 (m, 1H), 7.09 (m, 2H), 4.70 (m, 1H), 4.43 (q , J = 7Hz, 2H), 3.92 (d, J = 12Hz, 1H), 3.70 (m, 1H), 3.40 (m, 1H), 3.10 (m, 1H), 2.28 (m, 1H), 1.99 (m , 1H), 1.82 (m, 1H), 1.45 (s, 9H), 1.42 (t, J = 7 Hz, 3H), 1.21 (m, 2H).

B.1 7-([1α, 6α, 7α] -7-amino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4-difluorophenyl ) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

According to the method of Example 34B, the compound of Step A (283 mg, 0.51 mmol) was converted using hydrochloride to give the title product (150 mg, 0.322 mmol, 63% yield). Melting point 2040 ° C. (decomposition).

¹ H NMR (D ₂ O): 8.81 (s, 1H), 7.76 (d, J = 13.5Hz, 1H), 7.57 (m, 1H), 7.29 (m, 2H), 4.01 (d, J = 14.9Hz , 1H), 3.81 (bd, J = 13.3 Hz, 1H), 3.45 (m, 1H), 3.20 (m, 1H), 2.50 (bs, 1H), 2.05 (m, 1H), 1.79 (m, 1H) , 1.61 (bs, 2 H).

B. 2 7-([1α, 6α, 7α] -7-amino-3-azabicyclo [4.1.0] hept-3-yl) -6-fluoro-1- (2,4-difluorophenyl ) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate

According to the method of Example 34B, the compound of Step A (770 mg, 1.37 mmol) was converted to methanesulfonic acid in dioxane (10 ml) and water (10 ml) to give the title product (249.5 mg, 0.474 mmol, 35% yield). Got it. Melting point 219 ° C. (decomposition).

¹ H NMR (D ₂ O-NaOH): 8.35 (s, 1H), 7.93 (d, J = 13.4, 1H), 7.54 (m, 1H), 7.24 (m, 2H), 3.85-3.60 (m, 2H ), 3.33 (m, 1H), 3.06 (m, 1H), 2.85 (s, 3H), 1.95 (m, 2H), 1.63 (m, 1H), 1.00 (bs, 2H).

Example 45

A. 7-([1α, 6α, 7α] -7-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

According to the method of Example 34A, [1α, 6α, 7α] -7-tert-butoxycarbonylamino-3-azabicyclo [4.1.0] heptane (325 mg, 1.53 mmol) and 7-chloro-1- Ethyl ester of cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (402 mg, 1.29 mmol) was reacted to give the title product (609 mg, 1.25 mmol, yield 97%) was obtained.

¹ H NMR (CDCl ₃ ): 8.44 (s, 1H), 8.02 (d, J = 13Hz, 1H), 4.77 (bs, 1H), 4.35 (q, J = 7Hz, 2H), 4.25 (d, J = 13 Hz, 1H), 3.92 (m, 1H), 3.65 (m, 1H), 3.48 (m, 1H), 3.27 (m, 1H), 2.34 (m, 1H), 2.10 (m, 1H), 1.95 (m) , 1H), 1.40 (s, 9H), 1.37 (t, J = 7 Hz, 3H), 1.26 (m, 2H), 1.19 (m, 2H), 0.99 (m, 2H).

B. 7-([1α, 6α, 7α] -7-amino-3-azabicyclo [4.1.0] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride

According to the method of Example 34B, the compound of Step A (585 mg, 1.20 mmol) was converted using hydrochloric acid to give the title product (265.7 mg, 0.675 mmol, 56% yield). Melting point 180 deg. C (decomposition).

¹ H NMR (DMSO-d ₆ ): 8.58 (s, 1H), 8.40 (bs, 2H), 8.02 (d, J = 13.6 Hz, 1H), 4.19 (d, J = 14.1 Hz, 1H), 4.06 ( dd, J = 13.8, 5.2 Hz, 1H), 3.73 (m, 2H), 3.37 (m, 2H), 2.49 (m, 1H), 2.16 (m, 1H), 1.84 (m, 1H), 1.66 (m , 1H), 1.58 (m, 1H), 1.19 (m, 2H), 1.10 (m, 2H).

The pharmacological activity of the compounds of the present invention prepared as above was tested. The antimicrobial activity of the compounds of the present invention was tested according to the replication technique of the steer described above, and the results are shown in Table 1.

In addition, quinoline naphthyridine PD ₅₀ test was performed to test the toxicity of the compounds of the present invention, and the number of surviving mice for the test mice at each dose was measured. All experiments were performed with mice, and the pathogen was intraperitoneally. The drug was administered orally at 0.5 and 4 hours after pathogen administration. The results are shown in Table 2. These experimental results show that the test mice still survive when the compound of the present invention is administered at a high dose of 50 mg / kg.

Table 1 In Vitro Activity

TABLE 2 Quinolone / naphthyridine PD ₅₀ (mg / kg)

Note: ^* Control = untreated drug infected mice

^** Cip = shiftfloxacin treatment results under the same conditions

^*** Only test was performed at specific test = 50 mg / kg.

Claims (1)

A pharmaceutical composition for the treatment of bacterial infections comprising as an active ingredient a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof. Wherein R ¹ is hydrogen, a pharmaceutically acceptable cation, or a (C ₁ -C ₆ ) alkyl group, Y is independently ethyl, t-butyl, vinyl, cyclopropyl, 2-fluoromethyl, p-fluoro Phenyl or o, p-difluorophenyl, W is hydrogen, fluoro, chloro, bromo, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, amino or aminomethyl, A is CH, CF, CCl, COCH ₃ , C-CH ₃ , C-CN or N, or A together with Y and A and Y bonded carbon and nitrogen as carbons to form a 5- or 6-membered ring, which is oxygen Or may contain a double bond, R ^{8 which} is methyl or methylene may be bonded, and R ² is R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ are each independently H, CH ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ or CH ₂ NHC ₂ H ₅ , R ⁵ , R ⁶ , R ⁷ and R ⁹ may independently be NH ₂ , NHCH ₃ or NHC ₂ H ₅ , provided that R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and Three or less of r <^25> is other than hydrogen, and when three of these substituents are not hydrogen, at least 1 of these is methyl.